International Journal of Molecular Sciences Review GH/IGF-1 Abnormalities and Muscle Impairment: From Basic Research to Clinical Practice Betina Biagetti * and Rafael Simó * Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute and CIBERDEM (ISCIII), Universidad Autónoma de Barcelona, 08193 Bellaterra, Spain * Correspondence: bbiagetti@vhebron.net (B.B.); rafael.simo@vhir.org (R.S.); Tel.: +34-934894172 (B.B.); +34-934894172 (R.S.) Abstract: The impairment of skeletal muscle function is one of the most debilitating least understood co-morbidity that accompanies acromegaly (ACRO). Despite being one of the major determinants of these patients’ poor quality of life, there is limited evidence related to the underlying mechanisms and treatment options. Although growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels are associated, albeit not indisputable, with the presence and severity of ACRO myopathies the precise effects attributed to increased GH or IGF-1 levels are still unclear. Yet, cell lines and animal models can help us bridge these gaps. This review aims to describe the evidence regarding the role of GH and IGF-1 in muscle anabolism, from the basic to the clinical setting with special emphasis on ACRO. We also pinpoint future perspectives and research lines that should be considered for improving our knowledge in the field. Keywords: acromegaly; myopathy; review; growth hormone; IGF-1  1. Introduction  Acromegaly (ACRO) is a rare chronic disfiguring and multisystem disease due to Citation: Biagetti, B.; Simó, R. non-suppressible growth hormone (GH) over-secretion, commonly caused by a pituitary GH/IGF-1 Abnormalities and Muscle tumour [1]. The autonomous production of GH leads to an increase in the synthesis Impairment: From Basic Research to Clinical Practice. Int. J. Mol. Sci. 2021, and secretion of insulin-like growth factor-1 (IGF-1), mainly by the liver, which results in 22, 415. https://doi.org/10.3390/ somatic overgrowth, metabolic changes, and several comorbidities [1]. ijms22010415 One of the significant disabling co-morbidities accompanying ACRO is myopathy and its related musculoskeletal symptoms [2,3], which are significant determinants of the low Received: 4 December 2020 quality of life (QoL) of these patients and may persist despite disease remission [2,4–6]. Accepted: 28 December 2020 However, we do not know the exact underlying mechanisms involved in its develop- Published: 2 January 2021 ment. Although the duration of the disease and serum GH/IGF-1 levels were shown to be independent predictors of overall mortality and co-morbidities of ACRO [7–11], their spe- Publisher’s Note: MDPI stays neu- cific role in the pathogenesis of myopathy remains to be elucidated. Besides, both GH tral with regard to jurisdictional clai- and IGF-1 levels are not always directly and unequivocally associated with patient QoL ms in published maps and institutio- and the presence and severity of co-morbidities [4,12]. For this reason, numerous efforts nal affiliations. are currently being made to detect active disease, pointing to other variables apart from GH/IGF-1 [13,14]. Experimental research using cell lines and animal models is necessary to understand better the mechanisms involved in the myopathy induced by ACRO. In this regard, there is Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. some evidence regarding the effects of the GH/IGF-1 axis in the muscular system and the This article is an open access article mechanisms by which different conditions could impact on muscle performance. distributed under the terms and con- This review aims to describe the evidence regarding the role of GH and IGF-1 in ditions of the Creative Commons At- muscle anabolism, from the basic to the clinical setting, taking ACRO as the leading tribution (CC BY) license (https:// paradigm in the clinical setting. The new perspectives and scientific gaps in this field to be creativecommons.org/licenses/by/ covered are also underlined. 4.0/). Int. J. Mol. Sci. 2021, 22, 415. https://doi.org/10.3390/ijms22010415 https://www.mdpi.com/journal/ijms This review aims to describe the evidence regarding the role of GH and IGF‐1 in muscle anabolism, from the basic to the clinical setting, taking ACRO as the leading par‐ adigm in the clinical setting. The new perspectives and scientific gaps in this field to be Int. J. Mol. Sci. 2021, 22, 415 2 of 18 covered are also underlined. 2. GH/IGF‐1 Axis in Humans Pituitary2. synthesis GH/IGF-1and Axis in Humans secretion of GH is stimulated by the episodic hypothalamic Pituitary synthesis secretion of GH releasing factor and mainly and secretion inhabitedof GH is stimulated[15]. by somatostatin by the GHepisodic stimulateshypothalamic the synthesis of IGF‐1 mostly by the liver, and both circulating GH and IGF‐1 inhibit GH stimulates secretion of GH releasing factor and mainly inhabited by somatostatin [15]. GH secretion by the synthesis a negative of IGF-1 loop at bothmostly by the liver, hypothalamic andand both circulating pituitary GH and IGF-1 levels. In addition, age, inhibit GH secretion gender, pubertal byfood, status, a negative loop exercise, at both fasting, hypothalamic insulin, sleep and and pituitary body levels. play composition In addition, age, gender, pubertal important regulatory status, roles in the food, exercise, GH/IGF‐1 axis [15].fasting, insulin, sleep and body composition play important regulatory roles in the GH/IGF-1 axis [15]. 2.1. GH Circulation, GH Receptor and Intracellular Signalling 2.1. GH Circulation, GH Receptor and Intracellular Signalling In the circulation, GH binds to growth hormone binding protein (GHBP) which is a In the circulation, GH binds to growth hormone binding protein (GHBP) which soluble truncated form of the extracellular domain of the GH receptor (GHR) [16]. There‐ is a soluble truncated form of the extracellular domain of the GH receptor (GHR) [16]. fore, bound and free GH both exist in the circulation, and GH bioavailability depends on Therefore, bound and free GH both exist in the circulation, and GH bioavailability depends the pulsatile pattern of its secretion. on the pulsatile pattern of its secretion. GHR belongs to the so‐called “cytokine receptor family”, specifically part of the class GHR belongs to the so-called “cytokine receptor family”, specifically part of the class I cytokine receptor family. Cytokine receptors lack intrinsic protein tyrosine kinase (PTK) I cytokine receptor family. Cytokine receptors lack intrinsic protein tyrosine kinase (PTK) activity and therefore rely on binding non‐receptor PTKs for their signal transduction, the activity and therefore rely on binding non-receptor PTKs for their signal transduction, so‐called Janus Kinase (JAK) (Figure 1). The dimerisation induced by the binding of GHR the so-called Janus Kinase (JAK) (Figure 1). The dimerisation induced by the binding of is the critical step in activating the signalling pathway JAK/STAT (Janus kinase/signal GHR is the critical step in activating the signalling pathway JAK/STAT (Janus kinase/signal transducer and activator of transcription), and binding to GHR brings two JAK2 mole‐ transducer and activator of transcription), and binding to GHR brings two JAK2 molecules cules close enough to initiate their trans‐phosphorylation by recruiting STAT[17,18]. Phos‐ close enough to initiate their trans-phosphorylation by recruiting STAT [17,18]. Phosphory- phorylated STATSs, translocate lated STATSs, to theto translocate nucleus, binding the nucleus, to specific binding DNADNA to specific sequences and and induce sequences induce the transcription of specific GH‐dependent genes, thus promoting the transcription of specific GH-dependent genes, thus promoting not only not only the the synthe- synthesis of sisIGF‐1, IGF‐1 binding protein (IGFBP) acid‐labile sub‐units (ALS), but also of IGF-1, IGF-1 binding protein (IGFBP) acid-labile sub-units (ALS), but also directly directly stimulating proliferative stimulating and and proliferative metabolic actions metabolic (Figure actions 1). 1). (Figure Figure 1. Growth hormone (GH) receptor. The GH receptor’s dimerisation is the critical step in activating the signalling Figure 1. Growth hormone (GH) receptor. The GH receptor’s dimerisation is the critical step in pathway JAK/STAT. Phosphorylated activating the signallingSTATS pathwaytranslocate JAK/STAT.to thePhosphorylated nucleus, inducing the transcription STATS translocate toofthe specific GH-dependent nucleus, genes, promoting mainly the synthesis of IGF-1, IGFBP acid-labile sub-units, but also, stimulating inducing the transcription of specific GH‐dependent genes, promoting mainly the synthesis of other pathways (i.e., IRIS and SHC) that regulate IGF‐1, cellular proliferation, IGFBP acid‐labile sub‐units, butgrowth and metabolic also, stimulating otherevents. pathways In addition, (i.e., IRIS newly synthesised and SHC) that IGF-1 regulate promotes metabolic cellular and proliferation, cellular events. IGF-1:growth and metabolic insulin-like growthevents. factor,In addition, GH: growthnewly hormonesynthesised IGFBP3:IGF‐1IGF-1 binding protein type 3,promotes JAK/STAT: metabolic and cellular events. Janus kinase/signal IGF‐1: transducer andinsulin‐like growth transcription factor, activator GH: IRS: growth insulin hormone receptor substrate; PI3K: IGFBP3:3-kinase; phosphatidylinositol IGF‐1 binding protein type SHC: (adaptor 3, JAK/STAT: Janus kinase/signal transducer and transcription proteins). activator IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3‐kinase; SHC: (adaptor pro‐ teins). GHR is widely distributed throughout the body. Although GHR expression is particu- larly important in the liver, GH receptors are found in other tissues like muscle, fat, heart, kidney, brain and pancreas [19]. The actions of GH depend not only on the receptor but also on the organ it stimulates; specifically, GH actions in the muscle are controversial and depend, among other factors, on GH quantity, the time of exposition and the condition of the subjects. GHR is widely distributed throughout the body. Although GHR expression is par‐ ticularly important in the liver, GH receptors are found in other tissues like muscle, fat, heart, kidney, brain and pancreas [19]. The actions of GH depend not only on the receptor but also on the organ it stimulates; specifically, GH actions in the muscle are controversial Int. J. Mol. Sci. 2021, and22,depend, 415 among other factors, on GH quantity, the time of exposition and the condi‐ 3 of 18 tion of the subjects. 2.2. IGF‐1 Circulation, IGF‐1Circulation, 2.2. IGF-1 Receptor and Intracellular IGF-1 Receptor Signalling and Intracellular Signalling The majority of The IGF‐1 circulates majority in the of IGF-1 seruminasthe circulates a serum complex as awith the insulin‐like complex with the insulin-like growth growth factor‐binding factor-binding protein IGFBP and ALS. The function of ALS is tothe protein IGFBP and ALS. The function of ALS is to prolong half‐ the half-life of prolong life of the IGF‐I‐IGFBP‐ binary complexes, thus regulating IGF‐1 bioactivity the IGF-I-IGFBP- binary complexes, thus regulating IGF-1 bioactivity [20]. [20]. IGF‐I receptors (IGF‐1R) are highly IGF-I receptors homologous (IGF-1R) are highly tohomologous the insulin receptor. For this to the insulin rea‐ For this reason, receptor. son, at high concentrations insulin cross‐reacts with the IGF‐1R and vice versa [21]. In at high concentrations insulin cross-reacts with the IGF-1R and vice versa [21]. In cells cells expressing both expressing insulin and both IGF‐Iinsulin receptors and asIGF-I in thereceptors myocyte, as theinreceptors undergo the myocyte, thehet‐ receptors undergo ero‐dimerisationhetero-dimerisation (hybrid receptors), as well as homo‐dimerisation. In skeletal muscle IGF‐ (hybrid receptors), as well as homo-dimerisation. In skeletal muscle I receptors are mainly present asare IGF-I receptors hybrids, mainlytogether present as with an excess hybrids, of classical together with aninsulin excessre‐of classical insulin ceptors regarding other mammalian tissue. Hybrid receptors bind both receptors regarding other mammalian tissue. Hybrid receptors bind both insulin and IGF‐I,insulin and IGF-I, although they have a lower although insulin they haveaffinity a lowerthan classical insulin insulin affinity receptorsinsulin than classical [21,22].receptors [21,22]. In contrast to GHR, the IGF‐1R In contrast to GHR,is a member the IGF-1R of the is a receptor member tyrosine kinase (RTK) of the receptor tyrosine kinase (RTK) family. This typefamily. of receptor’s This type common characteristic of receptor’s common is characteristic to have an extracellular is to have an domain extracellular domain for ligand binding, for aligand single binding, transmembrane a singledomain and an intracellular transmembrane domain and domain with ty‐ domain with an intracellular rosine kinase activity, tyrosinewhich is activated kinase after the activity, which ligand binds is activated afterto the the extracellular ligand binds todomain, the extracellular domain, thus triggering the phosphorylation of Insulin Receptor Substrates thus triggering the phosphorylation of Insulin Receptor Substrates (IRS). Once the IRS is Once the IRS is (IRS). phosphorylated,phosphorylated, it activates different pathways it activates such as different phosphatidylinositol pathways 3‐kinase or such as phosphatidylinositol 3-kinase or RAS (Figure 2). RAS (Figure 2). Figure 2. Figure 2. IGF‐1 receptor, IGF-1 receptor, insulin and insulin receptor receptor andreceptor. hybrid hybrid receptor. Thereceptor The insulin insulin receptor (IS‐R), (IS-R), the the in‐ growth factor insulin-like sulin‐like growth factor receptor type I (IGF‐1‐R) and the hybrid receptor belong to receptor type I (IGF-1-R) and the hybrid receptor belong to the family of receptor tyrosine kinases. Thethe family of figure shows a receptor tyrosine kinases. The figure shows a certain degree of functional overlap. After binding certain degree of functional overlap. After binding ligands, the receptors stimulate the phosphorylation of tyrosine residues, ligands, the receptors stimulate the phosphorylation of tyrosine residues, which then induces which then induces phosphorylation of the Insulin Receptor Substrate (IRS) and SHC, which dock proteins for activating phosphorylation of the Insulin Receptor Substrate (IRS) and SHC, which dock proteins for activat‐ the phosphatidylinositol 3-kinase (PI3K-Akt) ing the phosphatidylinositol 3‐kinasepathway or the (PI3K‐Akt) Ras/MAPK pathway or the pathway, Ras/MAPK respectively. The PI3K-Akt pathway pathway, respec‐ is predominantly involved in metabolic actions (glucose uptake, insulin sensitivity) and cell tively. The PI3K‐Akt pathway is predominantly involved in metabolic actions (glucose uptake, proliferation, whereas the RAS/MAPK pathway, insulin is primarily sensitivity) and cellinvolved in mitogenic proliferation, whereaseffects (proliferation, the RAS/MAPK growth). pathway, The number is primarily of receptors alone is involved not the only determining in mitogenic factor effects in IGF-1 function. (proliferation, In this growth). Theregard, numberthe of assembly receptors and intracellular alone machinery is not the only deter‐ disposition are mining factor in IGF‐1 function. In this regard, the assembly and intracellular machinery disposi‐ also involved. tion are also involved. The number of IGF-1Rs in each cell is tightly regulated by several systemic and tissue factors, including circulating GH, thyroxine, platelet-derived growth factor, and fibroblast growth factor. Therefore, in vivo, the number of receptors alone is not the only determining factor in IGF-1 function [20] (Figure 2). Despite the ubiquity of IGF-1R, the in vitro biological effects of IGF-1 are relatively weak and often are not demonstrable except in the presence of other hormones or growth factors, thus suggesting that IGF-1 acts as a permissive factor augment the signals of other factors [22]. Furthermore, IGF-1 and insulin share common signalling pathways Int. J. Mol. Sci. 2021, 22, 415 4 of 18 and functional overlap. However, IGF-1 exerts a more decisive action than insulin in activating the RAS/MAP kinase pathway, which is related to cell growth, protein synthesis, and apoptosis. By contrast, insulin (and in lower grade IGF-1) regulates the metabolism of carbohydrates, lipids and proteins via PI-3K/Akt, [20,22] (Figure 2). 3. The Skeletal Muscle: A Central Link between Structural and Metabolic Function The skeletal muscle is one of the three significant muscle tissues in the human body, along with cardiac and smooth muscles [23]. It is crossed with a regular red and white line pattern, giving the muscle a distinctive striated appearance, leading to it being called striated muscle. There are three types of muscle fibres, which differ in the composition of contractile proteins, oxidative capacity, and substrate preference for ATP production. Type I fibres or slow-twitch fibres have low fatigability (better for endurance), and display slow oxidative ATP, primarily from oxidative phosphorylation (a preference for fatty acids as substrate) [24,25]. Type II or fast-twitch fibres have the highest fatigability, the highest contraction strength, while glucose is the preferred substrate [24]. They are further divided into Type IIa and IIb fibres. Type IIa is used for intermediate endurance contraction and, in general, relies on aerobic/oxidative metabolism. Both types I and IIa fibres are considered red fibres because of their high amounts of myoglobin. They also contain high numbers of mitochondria, Type IIb fibres, (also called IIX/d) or fast glycolytic fibres, are the fastest twitching fibres and are more insulin resistant [26]. They are also white fibres with low levels of myoglobin and a high concentration of glycolytic enzymes and glycogen stores. This is because they produce ATP primarily from anaerobic/glycolysis [27,28]. Thus, the fibre type composition of skeletal muscle impacts systemic energy consumption and vice versa. Endurance or aerobic exercise increases mechanical and metabolic demand on skeletal muscle, resulting in a switch from a fast-twitch to a slow-twitch fibre type [24]. In summary, skeletal muscle’s structural function is the most obvious one. It gives structural support, helps maintain the body’s posture, and exerts the muscle contraction leading to movements. Furthermore, skeletal muscle is also an important site of the intermediary metabolism: it is a storage site for amino acids, plays a central role in maintaining thermogenesis, acts as an energy source during starvation and, along with the liver and adipose tissue, is crucial in the development of insulin resistance in type 2 diabetes mellitus [29]. 4. GH/IGF-1 Actions in the Muscular System The muscle is a primary target of GH and IGF-1 [30,31]. The final contribution of GH and IGF-1 in any effect on the muscular system is not easy to establish in-vivo. Through its receptors, GH action can be both direct and indirect through the induced production of IGF-I. Furthermore, IGF-I is also produced locally in tissues and can act in a paracrine/autocrine manner [32,33]. As we commented above, the muscle is much more than an organ of support and contraction; it is a main metabolic organ. The fibre type composition of skeletal muscle impacts systemic energy consumption and vice versa [24]. Both hormones act in the muscle, modifying its metabolic function and structure. For example, Bramnert et al. (2003) [34] studied both the short-term (1 week) and long-term (6 months) effects of a low-dose (9.6 µg/kg body weight/d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism and muscle composition in 19 GH-deficient adult subjects. GH therapy resulted in glucose metabolism deterioration and an enhanced lipid oxidation rate in both short and long-term treatment groups, reflecting a fuel use switch from glucose to lipids. Furthermore, there was a shift toward more insulin-resistant type II X fibres in the biopsied muscles during GH therapy. These studies significantly increased our knowledge regarding the relationship between skeletal muscle and metabolism’s fibre type composi- tion. However, whether this muscular fibre shift represents the cause or the consequence of insulin resistance requires further investigation. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 5 of 18 apyboth both resulted short shortinand andglucose long-term long-term metabolism treatment treatment groups, groups, reflecting deterioration reflecting and an enhanced aa fuel fuel use use lipid switch switchoxidationfrom from glucose rate in to glucose to lipids. (9.6 bothlipids.μg/kg body weight/d) GH replacement short and long-term treatment groups, reflecting a fuel use switch from glucose to therapy or placebo on whole-body glucose (9.6 and(9.6 lipids. 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(EAA) of IGF-1 nitrogen expanded exposition. involved sug- The acute produc- techniques the action balance effects of gested that GH onmust could GH muscle be be inhibits kept different tissue stable is proteolysis to depending mainly maintain during on anabolic the fasting pool and of circumstances, has [35]. essential little Subsequent dose effect amino onand time proteolysis. studies (EAA) of involved exposition. have expanded Still, balance this The concept acute must beGH [36,37]. infusion kept of stable GH on to maintain amino acid the pool metabolism of essential results amino in acids aa radiolabelling profound (EAA) ininvolved reduction 1in thein tion have The ininfusion protein effects this by been the protein acute could concept of formation. skeletal used to formation. infusion be [36,37]. on muscle evaluate different amino ofConsidering GH isthe Considering on depending acid impaired metabolism this effects amino balance, in of this acid on the older GHbalance, and metabolism results different humans circumstances, IGF-1 in different aEAA and on results profound linked protein dose EAAinradiolabelling and withreduction aged metabolism. profound time techniques related reduction of exposition. amino Table techniques sar- inacid in aminoprotein GH acid is formation. the oxidation primary Considering hormone [36,37,39–41]. this in Somethebalance, fast different state; from EAA an radiolabelling evolutionary point techniques of view, Thehave copenia amino oxidation summarises have acute been GH been acid used [30]. infusion isusedthe the [36,37,39–41]. used to oxidation ofevaluate Therefore, results primary of to evaluate GH the GH/IGF-1 studies [36,37,39–41]. on amino hormone Some effects the studies actions assessing effects acid in of Some GHofstudies metabolism the fast demonstrated in GHand studiestheand protein state; demonstrated IGF-1 muscle anabolism IGF-1on demonstrated results from an that inprotein have on acute a using protein profound evolutionary that structural, that GHacute metabolism. radioisotopes. metabolism. acute GH infusion GH Table metabolic reduction point infusion increased infusion of in and The Table view, 1 1 have when summarises ageing action been of food whole-body increased summarises is whole-body the consequences GH on scarce,to evaluate protein results muscle the GH and results of changes synthesis protein tissue the studies vice of is effects versa. fuel without synthesis assessing mainly studies of GH consumption any without anabolic assessing proteinand significant any and protein IGF-1 from on significant anabolism has little anabolism protein carbohydrates changes using effect in changes metabolism. the on using and synthetic in radioisotopes. protein the proteolysis. radioisotopes. Table rate synthetictoThe Still,ofthe 1 mus- The aminoincreased when acid food whole-body oxidation isthe scarce, GHprotein [36,37,39–41]. changes synthesis Some fuel without studies consumption any demonstrated from significant carbohydrates that changes acuteand GHinprotein the synthetic infusion toThe the summarises use cle lipids, proteins. onallowing results Bydifferent contrast, of for studies the assessing isconservation other protein ofany vital anabolism protein stores using [38]. radioisotopes. Humans’ nitrogen rate action the rate increased use of action of muscle ofoflipids, effects GHcould of muscle whole-body GH proteins. muscle be on proteins. allowing muscle protein for By tissue Bythe contrast, depending tissue contrast, synthesis isstudies mainly conservation other mainly otheron without using studies anabolic the anabolic studies vital higher and ofcircumstances, using hasdoses and using significant protein higher little has higher of dose little GH doses effect doses changes stores and effectfound on [38].on of of in GH on GHthe Humans’ lower proteolysis. time of found exposition. proteolysis. found synthetic proteolysis lower Still,Still, lower nitrogen action balance rates. proteolysis 4.1. the The GH effects acute of GH must In could on rates. infusion be general,be muscle kept Inof acute general, different GH tissue stable GH onto to is acute depending amino mainly maintain infusion GH anabolic the exerted infusion on acidinfusion the pool metabolism an and of exerted circumstances, has essential anabolic an results little amino effect anabolic dose effect in adose on and acids effect profound time proteolysis. whole-body (EAA) onof whole-bodyinvolved Still, amino-acid exposition. rate ofthe proteolysis balancemuscleeffects must could rates. proteins. be be In kept begeneral, By different stablecontrast, depending acute GH other maintain studies the onpool the usingcircumstances, exerted higher of essential an anabolic doses amino and found effect ofacids GH onreduction time (EAA) oflower exposition. whole-body involved in the Thein amino effects protein (AA) amino-acid acuteacid could formation. metabolism, (AA) infusion oxidation different metabolism, of on GH Considering evidenced depending onanabolic [36,37,39–41]. in evidenced amino this reduced acid Some on in the balance, leucinecircumstances, reduced metabolism studies different oxidation, leucine results demonstrated EAA dose oxidation, in ain and radiolabelling increased profound that time acuteincreased of nonoxidative exposition. techniques reduction GH nonox- infusion leucine in in The proteolysis The amino-acid in protein acute first rates. infusion reports (AA) In formation. of metabolism, general, GH theacute Considering on amino evidenced GH growth infusion this acid in balance, metabolism hormone reduced exerted differentanleucine results effects anabolic dated oxidation, effect EAAinradiolabelling a profound back on to 1948 increased whole-body reduction and nonox- techniques sug- The have idative amino increased acute disposal, been acidleucineinfusion used oxidation whole-body to of anmetabolism, increased disposal, GHan evaluate onincreased amino [36,37,39–41]. protein amino the acid effects synthesis acid Some amino metabolism disappearance ofreduced GHacid studies without andany rate IGF-1 results disappearance demonstrated (Rd) significant on (allprotein athatprofound indexes rate changes of metabolism. (Rd) acute in reduction protein (all GH the indexes synthesis) Table infusion synthetic in of1 gested amino-acidamino idative have been that acid leucine (AA) GH used oxidation inhibits disposal, to evaluate [36,37,39–41]. proteolysis an increased evidenced the effects during Some amino in of GH fasting studies acid [35]. demonstrated Subsequent disappearance leucine and demonstrated oxidation, IGF-1 on protein rate that studies (Rd) increased acute metabolism.have (all GH expanded indexes nonox- infusion Tableof 1 amino and summarises protein acid less synthesis)oxidation effect the on results and [36,37,39–41]. protein of less breakdown studies effect on Some assessing (a protein studies lower proteinrate breakdown of amino anabolism(a acid that using acute appearance GH radioisotopes. (Ra)) infusion probably The increased rate of protein this idative muscle increased concept leucine summarises whole-body synthesis) proteins. whole-body [36,37]. disposal, the andan results protein By less contrast, protein synthesis effect increased of studies on other synthesis amino without protein assessing studies without acid any using breakdown disappearance protein significant any higher anabolism (a lower significant lower rate changes doses using rate rate (Rd) of of inamino (all the ofradioisotopes. changes GH found in the amino indexes acid synthetic lower synthetic acid ofThe ap- ap- increased actionrelated pearance rate of muscle whole-body ofismuscle GH with (Ra)) on dosage. muscle probably proteins. protein Regarding tissue related synthesis iswith chronic mainly without dosage. GH anabolic any exposure, and Regarding significant has it seems little chronic changes effect more GH ofon infound consistentthe synthetic proteolysis. exposure, it than seems Still,acute proteolysis protein rate pearance action GH of synthesis) of GH rates. (Ra)) theon In primary andmuscle lessBy general, proteins. probably contrast, By hormone effect tissue acute related on is GH contrast, inother with protein mainly infusion the other dosage.studies fast studies breakdown anabolic state; using exerted Regarding and using from (ahigher an has anabolic an lowerhigher chronic doses evolutionary little rate effect effect doses GH of on GH on of exposure, amino GHwhole-body point proteolysis. acid itlower found of seems view, ap- lower Still, rate the more proteolysis amino-acid of effectsmuscle administration consistent could rates. (AA) proteins. be than In indifferent acute general, metabolism, By promoting contrast, dependingan administration acute evidencedGH other increase on infusion studies the in in ininfusion reducedpromoting exerted using whole-body circumstances, an leucine higher an protein dose increase anabolic doses and effect of synthesis in GH time whole-body on found of[42–44]. exposition. whole-body lower Similar pro- when more pearance the proteolysis food consistent (Ra))could effects is rates. scarce, probably than be Inrelated GH general, acutechanges acute fuel administration with GH consumption dosage. in promoting Regarding exerted from an chronic anoxidation, anabolic carbohydrates increase GH and increased ineffect and exposure, on protein whole-body nonox- whole-body itexposition. seems topro- the proteolysis The tein results amino-acid idative acute synthesis leucine rates. have infusion (AA) [42–44].Indifferent been general, of metabolism, disposal, reported GH Similar an depending onacute after amino results evidenced increased GHamino GH acid have on infusion the been reduced acid circumstances, inadministration metabolism exerted reported anin results leucine disappearance after dose anabolic patients inGH oxidation, a[38]. rate effect profound time with on administration (Rd)increased (all ofwhole-body growth reduction indexes hormone in nonox- pa- ofin in moreuse tein amino-acid of lipids, synthesis consistent Thedeficiency acute infusion than(AA) allowing [42–44]. metabolism, acute for Similar of [45,46], the administration GH on amino evidenced conservation results have acid in of in been promoting metabolism reduced vital protein reported an leucine stores after increase resultsinoxidation, oxidation, GH in inmalnourished Humans’ administration a profoundwhole-body increased reductionnitrogen pro-in nonox- pa- amino-acid amino tients acid with (AA) (GHD) oxidation growth metabolism, hormone[36,37,39–41]. evidenced and after Some GH in reduced administration studies leucine demonstrated that increased acute GHpatients nonox- infusion under idative protein tein idative balance tients synthesis amino leucine synthesis) withmust acid leucine be growth [42–44].disposal, oxidation and keptdisposal, stable hormone Similar an effect less to deficiency increased an results [36,37,39–41]. onhave increased maintain deficiency amino protein Some the(GHD) amino (GHD) been acid breakdown pool [45,46], disappearance acid of reported studies essential [45,46], (a after demonstrated and disappearance and lowerafter amino GH after raterateGH (Rd) rate acids GH administration that ofadministration (all (all amino (Rd) (EAA) administration acute GH indexes acid pa-ap- indexes involved in infusion ofinin of idative protein pearance haemodialysis increased malnourished leucine whole-body synthesis) (Ra)) patients probably [47].less disposal, and underan protein increased effect related synthesis haemodialysis on with amino protein dosage. without acid [47]. breakdown Regarding disappearance any significant (a lower chronic rate changes rate GH (Rd) of in amino exposure, (allthe indexes synthetic acid it seems ap- ofap- in protein malnourished tients with growth increased synthesis) formation. whole-body patients hormone and under proteinless Considering effect haemodialysis deficiencysynthesis on this(GHD) protein balance, without [47]. breakdown different [45,46], any and EAA significant (a lower after radiolabelling GH changes rate of administration in amino the techniques syntheticacid in protein rate of synthesis) muscle and proteins. less effect Byhaemodialysis contrast, on otherprotein breakdown studies usingan (a increase higher lower doses rate ofofGH amino found itacid ap- pearance more have pearance malnourished rate ofbeen (Ra)) consistent muscle used(Ra)) patientsprobably than to proteins. acute probably evaluate under related By related the contrast, with administration effects withdosage. other of in dosage. GH [47]. studies Regarding promoting and Regarding IGF-1 using chronic on higher chronic protein GH doses inexposure, GH whole-body exposure, metabolism. of GH found itlower seems Tablepro- lower seems 1 Table Table 1. Most pearance relevant (Ra)) studies probably with GH related evaluatingwith protein dosage. anabolism Regarding usingchronicradioisotopes.GH exposure, itin seems Table 1. 1. Most more tein Most relevant proteolysis consistent synthesis relevant more summarises studies rates. studies consistentthe with than [42–44]. Inthan with results GH general, acute Similar GH of evaluating evaluating acutestudiesacute administration results protein GH administration have protein assessing anabolism infusion in been anabolismin protein exerted promoting reported using promotingusing an anabolism radioisotopes. afteranabolic increase an GH radioisotopes. increase using effect in administration in on whole-body whole-body whole-body radioisotopes. pro- pa- The pro- proteolysis more consistent rates.than In general, acute acute GH infusion administration inreduced exerted anananabolic promoting increase effect on whole-body in whole-body pro- Author Table 1. Most Subjects amino-acid tein tients relevant action synthesis tein with studies ofsynthesis GH (AA) growth[42–44]. with on metabolism, GH [42–44]. muscle Design Similar hormoneevaluating Similar tissue isevidenced results deficiency protein results mainly GH have (GHD)in been anabolism Dose have anabolic beenreported [45,46], using and leucine and after radioisotopes. reported has Effectslittle oxidation, afterGH aftereffect GH increased administration onadministration proteolysis. Conclusions nonox- in pa-in pa- in Still, Author Author Subjects Subjects amino-acid Design(AA) Design metabolism, GH evidenced GH Dose Dose in reduced Effects leucine Effects oxidation, Conclusions increased Conclusions nonox- tein idative tients synthesis malnourished leucine withwith growth [42–44]. disposal, patients hormone Similar under an results increased deficiency haemodialysis have amino (GHD) been [47]. acid reported disappearance [45,46], and afterafter GH rate GH administration (Rd) (all administration indexes in pa- inof in the tients effects idative could leucine growth be disposal, hormone different 0.014 anGH 0.014 depending increased deficiency μg/kg/min μg/kg/min on amino the(GHD) Rd acid Rd PHe [45,46], circumstances, disappearance PHe and dose after and Locally rate Locally GHtime (Rd) administration infused of exposition. GH (all indexes infused GH sti- sti- of Author Fryberg Subjects tients Brachial protein Design with growth artery synthesis) infusion hormone andGH less effect Dose 0.014 deficiency µg/kg/min onacid protein (GHD) Effects [45,46], breakdown Rd PHe and after (a lower GHConclusions Locally infused administration rate ofskeletal amino GH acid ap- in Fryberg Fryberg 77 healthy malnourished The Brachial malnourished acute artery Brachial infusionpatients infusion artery patients of under To under on rise haemodialysis amino haemodialysis locally not [47]. metabolism [47]. BCAAs results in a profound mulates reduction muscle in [39] healthy protein 7 healthymalnourished no synthesis) patients and 0.014 less under effect Toμg/kg/min riseTo locally on rise locally haemodialysis protein not not breakdown Rd[47]. BCAAs PHe BCAAs (a lowerLocally rate mulates of stimulates infused amino skeletalGHskeletal acid muscle sti- ap- muscle [39] [39] Fryberg Table 1. Most no placebo pearance relevant Brachial amino placebo (Ra)) studies infusion artery acid infusion oxidation probably with GH no placebo related evaluating with protein dosage. anabolism Regarding chronic using radioisotopes. GH exposure, it seems 7 healthy pearance (Ra)) probably To[36,37,39–41]. systemic related systemic rise systemic locally notSome with dosage. studies BCAAs release Regarding release demonstrated release chronic mulates that protein GH protein acute exposure, protein GH synthesis. synthesis. synthesis. skeletal muscle infusion it seems [39] Table 1. Most Table 1.no more relevant Most placebo increased consistent relevant studies studies whole-body than with GH with acute evaluating GH protein administration evaluating protein synthesis protein inanabolism anabolism without promoting using using anradioisotopes. increase radioisotopes. in whole-body pro- Author Subjects Table 1. Most moreBrachial relevantconsistent Brachial artery artery infusion Design studies than infusion withsystemic GH GH acuteGH 0.014 0.014 evaluating GH GH μg/kg/min administration μg/kg/min Doseprotein release anabolism 33 h in promotinghanyRd significant using an RdEffects increase protein radioisotopes. changes GH synthesis. blunted in the synthetic inConclusions whole-body the action pro- of Fryberg tein rate 33 hofsynthesis GH muscleand then[42–44]. 33 h proteins. Similar Insulin By contrast, results 0.02 mU/kg/min other have been studies 66 h reported Rd using higher after GH doses GH administration blunted ofConclusions GH the found action in lower pa- of Fryberg Author Author 77 healthy Subjects Subjects tein Brachial h GH synthesis and Design artery Brachial then [42–44]. infusion Design h GH Insulin Similar 0.014 arteryhormone 0.0140.014 GH0.02 results μg/kg/min μg/kg/minGH mU/kg/min Dose have Dose µg/kg/min 3been h RdRd hPHeRd reported 3Effects h RdEffects after GH Locally administration insulin infusedConclusionsGH in sti- pa- Fryberg healthy tients Brachial with artery growth infusion deficiency (GHD) [45,46], and after GH GH insulin blunted administration GH blunted the actionthe of action in [40] [40] Author Fryberg Fryberg 7 healthy GH and Subjects 3proteolysis tients h GH ++ insulin/no with Design rates. insulin/no then infusion growth3 h3In pla- pla- h GH general, hormoneToTo Torise 0.014 Insulin and rise rise locally acuteGH locally locally μg/kg/min 0.02 0.014 deficiency Dose GH mU/kg/min μg/kg/min Insulin not not not 0.02 syste- infusion syste- (GHD)6 hRd Ra Ra BCAAs Rd exerted PHe [45,46], Rd6 PHe h Effects Rd anand anabolic after mulates Locally to to effect GHLocally suppress Conclusions suppress oninfused skeletal infused whole-body administration muscle GH proteolysis proteolysis sti- sti- GH inof [39] Fryberg Fryberg noceboplacebo Brachial malnourished 7 healthy 7 healthyamino-acid artery Brachial(AA) arteryinfusion patientsinfusion under mic 0.014 haemodialysis μg/kg/min [47]. BCAAs Rd PHeleucine oxidation, insulin insulin Locally infused GH sti- [40]Fryberg [40] 7 healthy 7 healthy GH cebo + insulin/no malnourished Brachial thenartery 3 pla- metabolism, hpatients GH infusion +ToTo mic rise under rise systemic locally To evidenced locally mU/kg/minnotnot haemodialysis rise locally syste-not inRa reducedBCAAs BCAAs release [47]. BCAAsRa mulates protein mulatesincreased skeletal synthesis.skeletal musclenonox- muscle [39] [39] 7 healthy no placebo no placebo To rise locally not BCAAs to suppress to Similar mulates suppress proteolysis muscle skeletal proteolysis size, muscle Yarasheski 18 idative ceboBrachial leucine insulin/no artery disposal, infusionplacebo mic ansystemic systemic GH increased 0.014 To rise locally μg/kg/min amino not BCAAsacid release 3protein h Rd disappearance release synthesis rate Similar protein (Rd) protein muscle(all synthesis. indexes synthesis.size, of [39] Yarasheski 18 healthy Table 1. Most no healthy Resistance placebo Resistance relevant training training studies with GH GH GH 40 evaluating systemic μg/d 40systemic μg/d protein anabolism protein release BCAAs synthesis using radioisotopes. GH blunted strength protein and the synthesis. actionsynt- protein of Fryberg [44] man Table 1. protein Most 3 h GH Brachial relevant synthesis) and artery then studies Brachial artery infusion GH/placebo 3 h infusionand with GH less Insulin GH effect 0.014 evaluating GH 0.02 on μg/kg/min protein mU/kg/min protein 0.014 μg/kg/min breakdown 6 3 anabolism h Leu. Rd using 3 synthesis hOx Rd (a lower Similar radioisotopes. rate strength of muscle amino and protein size, acid ap- synt- [44] Yarasheski man 18 7healthy healthy GH/placebo Resistance Brachial training artery infusion GH for for 40 μg/d GH 12 12 0.014 weeks weeks μg/kg/min protein Leu. 3hhRd Rd Ox GH insulin hesis blunted GH blunted the action the action of of [40] Fryberg Fryberg Author Subjects pearance3GHh GH +h 3 GH (Ra)) insulin/no and then Design and probably pla- 3 h 3 hInsulin then To related rise Insulinlocally 0.02 GH with not mU/kg/min 0.02 Dose dosage. syste- 6Ra mU/kg/min Regarding 6 h RdEffects protein chronic strength hesis GH GH exposure, and blunted protein Conclusionsthe actionitsynt- seems of [44]Fryberg Author man7 healthy 7 Subjects healthy GH/placebo 3 hGH Design for 12 weeks GH Dose Leu. Ox Effects to insulin Similar suppress insulin muscle proteolysis Conclusions size, [40] [40] Yarasheski 7 18 healthy healthy morecebo GH +GH +and Resistance insulin/no consistent thenpla- insulin/no 3training than hpla-acuteInsulin mic To rise 0.014To GH 0.02 locally 40mU/kg/min administration μg/kg/min rise locallyµg/d not syste- not in syste- 6Rd BCAAs Ra hRa promoting Rd PHe synthesis an increase hesis Locally insulin in whole-body strength infused and GH sti- protein pro- Fryberg [40] [44] man Brachial GH + insulin/noartery infusion GH/placebo pla- Similar 0.014 To rise μg/kg/min locally not syste- Rd PHe Ra toLocally suppress to suppress infusedproteolysis proteolysis GH sti- Fryberg 7 healthy teincebo synthesis cebo Brachial artery [42–44]. infusion mic Tomic risefor 12 weeks results locally have not been BCAAs reported BCAAs BCAAs after GH Similar mulates to muscle administration synthesis suppress skeletal size, proteolysis in pa- muscle Yarasheski [39] 187 healthy Resistance no cebo placebo training GHTo mic 40 rise μg/d locally not protein BCAAs synthesis Leu. Ox mulates skeletal muscle [39] tients with no placebo growth hormone systemic deficiency (GHD) release [45,46], and after strength Similar protein GH and muscle protein synthesis. administration Similar muscle size,size, synt- in Yarasheski [44] Yarasheski 18 man healthy 18 healthy Resistance GH/placebo Resistance training training GH for 1240weeks systemic GH μg/d 40 μg/d Leu. protein Oxsynthesis protein release synthesis protein muscle Similar synthesis. size, Brachial artery infusion GH40 0.014 μg/kg/min [47]. 3 h RdLeu Ra in hesis strength strength and protein and protein synt-synt- Yarasheski [44] 18 man healthy malnourished Resistance GH/placebo patients training under GH for 12 weeks haemodialysis μg/d protein Leu.Leu. Ox Ox synthesis GH blunted the action of [44] man GH/placebo Brachial artery infusion GHfor 12 weeks 0.014 μg/kg/min 3 h Rd either the strength hesis and protein synt- Fryberg 3 h GH and then 3 h for Insulin0.018 0.02IU/kg/day mU/kg/minfor 6 h Rd GH hesis blunted [44] Fryberg man 7 healthy GH/placebo 3 h GH Double-blind, and then 3 h 12 weeks Insulin 0.02 mU/kg/min Leu. Ox 6 h Rd GH insulin placebo or GH- hesis actionthe action with in adults of [40] Russell-Jones 7 healthy Table 1. Most GH + relevantinsulin/no studies pla- with GH To 1 rise month locally evaluating followed not proteinsyste- by Ra anabolism using insulin radioisotopes. [40] [45] 18 adults GHD placebo-controlled GH + insulin/no pla- To rise0.036locally not syste-for Ra treated toGHD is due suppress to an increase proteolysis cebo trial mic IU/kg/day BCAAs to in suppress proteolysis cebo Design mic 1GH BCAAs protein synthesis. Author Subjects Dose month InEffects GH group Conclusions Similar muscle size, Yarasheski 18 healthy Resistance training GH 40 0.014 μg/d μg/kg/min protein Rd PHe synthesis Locally Similar muscle size, infused GH sti- Yarasheski Fryberg 18 healthy Resistance Brachial training artery infusion GH 40 μg/d Leusynthesis protein Rd strength and protein synt- [44] 7man healthy GH/placebo Toforrise 12 weeks locally not Leu. Ox BCAAs strengthskeletal mulates and protein musclesynt- [44] [39] man GH/placebo no placebo for 12 weeks Leu. Ox hesis systemic release hesis synthesis. protein Brachial artery infusion GH 0.014 μg/kg/min 3 h Rd GH blunted the action of Fryberg 3 h GH and then 3 h Insulin 0.02 mU/kg/min 6 h Rd 7 healthy insulin [40] GH + insulin/no pla- To rise locally not syste- Ra to suppress proteolysis cebo mic BCAAs ucose metabolism deterioration ageing and an consequences enhanced The first lipid reports and onvice oxidation the versa. rate anabolic in growth hormone effects dated back toincreased 1948 and proteolysistype gested gested amino-acid increased more rates. when summarises The amino biopsied that that consistent summarises In composition. food GH first acid general, GH (AA) whole-body is the inhibits reports scarce, inhibits oxidation muscles than the acute However, results GH on metabolism, proteolysis acute results GH the proteolysis during protein changes of anabolic [36,37,39–41]. evidenced GH synthesis administration of infusion whether studies ageingstudies fuel during growth during this Some therapy. fasting in without assessing exerted in an muscular consumption assessing consequences hormone fastingstudies reduced These[35]. promoting protein [35]. any protein anabolic fibre from and Subsequent effects Subsequent demonstrated leucine studies significant an shift dated oxidation, increase anabolism effect on studies changes represents carbohydrates anabolism vice versa. using back studies that significantly in using whole-body and have to in the 1948 have acute increased the whole-body expanded radioisotopes. cause protein radioisotopes. and expanded GH synthetic or toThe pro-sug- sug- infusion nonox- the our The ng-term treatment groups, reflecting this gested this idative rate gested concept concept increased knowledge of a thatfuel leucine muscle that GH useGH [36,37]. switch inhibits [36,37]. whole-body disposal, regarding proteins. inhibits Byanfrom proteolysis protein the glucose proteolysis increased relationship contrast, during synthesis to during amino other fasting fasting without acid between studies [35]. using [35]. any disappearance skeletal Subsequent Subsequent significant higher muscle rate doses studies studies changes (Rd) and of GH have (all inhave metabolism’s found expanded the indexes expanded synthetic lower offibre ment therapy or placebo amino-acid on whole-bodytein (AA) consequence use action 4.1. thisofGHsynthesis actionmetabolism, lipids, of glucose ofGH [42–44]. insulin allowing on muscle evidencedSimilar resistance for the tissue in results is reduced requires conservation have mainly of GH on muscle tissue is mainly anabolic and has little effect on proteolysis. Still, been leucine further of anabolic vital reported and oxidation, investigation. protein after has GH little increased stores [38]. administration effect nonox- Humans’on proteolysis. nitrogenin pa- Still, this protein GH concept rate type proteolysis GH concept of isis the muscle synthesis) composition. [36,37]. the rates. [36,37]. primary primary Inproteins. and hormone less However, general, hormone By effect acutecontrast, onin whether GH the inbeenthe protein fast other fast this infusion state; state; studies breakdown muscular exerted from from using an (a fibre an an evolutionary evolutionary higher lower shift anabolic doses rate represents effect of point on point GH ofadministration amino theof ofof found acid cause view, view, lower ap- orinthe osition H in 19 GH-deficient replacement idative therapy or leucine adult tients subjects. balance the placebo the effects on with disposal, Moreover, effects mustGHcould growth whole-body an be could ther- increased GH/IGF1 kept be hormone be different stable different glucose amino levelsto 4.1. deficiency depending have maintain depending GH acid the on (GHD) on disappearance related pool the the of[45,46], circumstances, to circumstances, rate ageing. essential and (Rd) In aminoafter dose (all dose particular,GHand indexes acids and time ofwhole-body time IGF-1 (EAA) of exposition. produc- involved exposition. , there was a shift toward more when when pearanceinsulin-resistant amino-acid The GHfood food proteolysis consequence GHfirst is is (Ra)) the is (AA)isreports the scarce,primary scarce, rates. probably of type GH on primary GH In insulin metabolism, II the X changes hormone changes general, related fibres anabolic hormone resistance fuel acute with evidenced in in fuel the growth in dosage. requires the consumption the fast consumption GH hormone infusion in reducedfast state; Regarding further state; from from from exerted effects fromanan chronic investigation. leucine dated an carbohydrates evolutionary carbohydrates anabolicGH back evolutionary and to and effect exposure, 1948 protein point point protein on and of to sug- ofthe view, to whole-body it seems theview, rioration uscle and an enhanced composition inprotein 19 GH-deficient inmalnourished synthesis) lipidtion The The oxidation by protein acute and the adult acute rate skeletal formation. infusion subjects. patients lessinfusion effect in muscle ofGH on under of Considering GH GH protein is on ther- haemodialysis on breakdown impaired amino amino this acid inbalance, acid older [47]. metabolismmetabolism (ahumanslower different rate and resultsEAA ofoxidation, results inamino linked inwithaacid radiolabelling a growth profound increased profound aged ap- related techniques reduction nonox- reductionsar- in datedin s during GH therapy. These gested use when use more idative studies when ofof amino-acidthat lipids, food lipids, consistent GH food Moreover, leucine issignificantly inhibits is allowing scarce, allowing (AA) scarce, than disposal, GH GH/IGF1for forGH metabolism, acute an increased proteolysis the changes the changes The conservation fuel conservation administration levels increased first our during fuel evidenced haveamino reports fasting consumption consumption been of in of in vital vital on [35]. reduced promoting related acid the protein from protein to disappearance anabolic Subsequent from carbohydrates stores carbohydrates leucine an ageing.stores increase In ratestudies [38]. [38]. oxidation, in Humans’ particular, (Rd) and hormone Humans’have and whole-body protein increased (all expanded protein IGF-1 indexes effects nitrogento nitrogen theto nonox- pro- produc- of the back to 1 ups, reflecting bolism Int. J. Mol. deterioration a fuel pearance Sci. usean 2021, and switch 22, (Ra)) 415 copenia have amino enhanced fromamino probably been glucose [30]. acid lipid acid used oxidation oxidation relatedto evaluate Therefore, to oxidation with [36,37,39–41]. dosage. GH/IGF-1 [36,37,39–41]. rate the in effects Regarding actions Some ofGH Some GHin studiesthe andstudies chronic muscle IGF-1 demonstrated GH demonstrated have on exposure, structural, protein that itacute thatmetabolism.seems acute metabolic GH GHTable infusion infusion and1 6 of 18 ding the relationship between Tableconsistent 1. Most teinskeletal this balance use balance protein concept use of idative synthesis tion relevant of must lipids, by muscle must [36,37]. lipids, leucine the synthesis) studies bebe [42–44]. skeletaland allowing kept allowingkept metabolism’s stable disposal, and with Similar muscle GHless for to forevaluating stable the gested an effect the maintain conservation toversa. ismaintain increased results impaired on that fibre conservation have the protein protein the amino in inhibits pool of beenpool older of vital breakdown anabolism of proteolysis vital essential protein ofhumans acid reported protein essential disappearance using (a amino stores after and during stores amino lower GH linked radioisotopes. acids [38]. rate acids rate fasting [38]. (EAA) Humans’ administration with of Humans’ (EAA) (Rd) aminoaged [35]. (all Subsequent involved nitrogen involved indexesnitrogen insynthetic related acid pa-sar- ap- of studies ha atment groups, more reflecting a fuel ageing summarises increased use increased thanswitch acute consequences the whole-body whole-body from administration results and glucose ofvice protein protein studies to in synthesis synthesis promoting assessing without without an protein increase anyfrom any anabolism significant in significant whole-body using changes changes pro- radioisotopes. in the in the synthetic The . However, whether this muscular in tients pearance fibre inIIprotein balance GH balance protein copenia with shift is must (Ra)) the must formation.represents be formation. synthesis) growth [30]. primary be kept probably kept the hormone stable Considering stable Considering and hormone Therefore, less related this cause toconcept todeficiency maintain effect GH/IGF-1 with or inthis onthe the maintain this [36,37]. fast balance, the balance, dosage.protein (GHD) actions the poolstate; inpool different of of theessential different breakdown [45,46], Regarding muscle andan essential EAA EAA chronicevolutionary amino (a amino radiolabelling lower after have GHGH acids radiolabellingrateacids point (EAA) ofGH administration structural, exposure, (EAA) amino of techniques view, involved techniques metabolic it involved acid seems in ap- and ard more insulin-resistant tein synthesis type action rate rate [42–44]. Xoffibres of of GH muscle muscle Similar in the onproteins. muscle proteins. results tissue By haveBy iscontrast, contrast, been mainly reported other other anabolic studies studies after and GH using using has little higher higher administrationeffect doses doses onof in ofpa- proteolysis. GH found found Still, lower lower nsulin Author resistance requires Subjectsfurther when have in have investigation. inbeen protein pearance malnourished more ageing food protein been consistent Design is used scarce, formation. formation. used(Ra)) to to patients consequences than GH evaluate changes Considering Considering evaluate probably under acute and the the related GH GH fuel effects effects haemodialysis vice administration Dose thisisof with versa. the consumption this GH balance, of GH dosage. in primary balance, and [47]. and promoting from different Effects hormone different IGF-1 IGF-1 Regarding carbohydrates on an EAA on EAAin protein the radiolabelling protein chronic increase fast Conclusions and radiolabelling metabolism. metabolism. GH in state; protein exposure, whole-body from techniques to Table it pro-an the techniques Table 1 seems 1 evolutionary po y. a These shift toward studiesmore tients with4.1. significantly insulin-resistant growth the GH proteolysis proteolysis increased effects hormone type could rates. 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GH acids (Rd) infused Acute Conclusions (all administration (EAA) GHindexes GH did involved sti-not of in affect Yarasheski hibits Fryberg 18 healthy proteolysis during fasting The[35].Resistance acute rate Brachial proteolysis of Subsequent training infusion muscle artery rates. of GH proteins. studies infusion In GH on have the 40 By effects μg/d amino contrast, expanded acidcould be metabolism other different protein studies depending synthesis results using in higher aGH on profound doses the blunted of circumstances, the GH action reductionfound of in lowerdose and time o Fryberg 77man healthy rate proteolysis protein3 use malnourished of GH muscle of hmalnourished lipids, and synthesis) rates. thenproteins. patients3Inhgeneral, allowing and general, patients By Insulin To less under for acute contrast, under rise 0.014 acute effectthe 0.02 locally GH GH conservationinfusion other haemodialysis mU/kg/min μg/kg/min on haemodialysis not protein infusionstudies 6ofexerted BCAAs breakdown [47]. using hexerted vital [47]. 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Subsequent Author growth 718healthy ceboSubjects healthy hormone studies effects tein action 3Resistance dated hsynthesis haveGH Brachial ofbackexpanded GH then mic onartery [42–44]. training muscle Design to 1948 hinfusion and Insulin tissue GH sug- 40rate 0.014 results is μg/d mainly of mU/kg/min GHμg/kg/min BCAAs have muscle anabolic Dose been 6protein proteins. hreported Rd and h Rdhas By after little synthesis Effects contrast, GH otheradministration insulin on GH proteolysis. studies bluntedConclusions using the in pa- of 1doses of GH Still, higher action wing Author for the conservation Subjects of proteolysis vital pearance protein pearance protein protein Design (Ra)) rates. synthesis) stores synthesis) (Ra)) In [38]. probably and probably Prospective andgeneral, and Humans’ 3 hcross less related less acute effect related GH effect with GH Dose nitrogen onnot with on infusion dosage. protein protein dosage. exerted breakdown Regarding breakdown Regarding Effects an anabolic chronic (a (a lower chronic lower GH effect rate GH strength rate exposure, of on of Conclusions amino exposure, and Increased whole-body amino protein it seems acid it seems muscle acid synt-ap- ap- protein [40] [44] Fryberg man7[35]. tients the GH summarises 3+with effects GH/placebo hinsulin/no GH growth could the be pla- then results hormone different To for 12of rise Insulin studies locally deficiency depending weeks 0.014 0.02 μg/kg/min assessing on syste- mU/kg/min (GHD) the Ra Leu. protein 6Ox [45,46], circumstances, Rd h Rd PHe anabolism Similar and muscle after dose GH and using size, radioisotopes. administration time Locally of exposition. infused GH in The sti- olysis during 18 healthy fasting healthy Subsequent Resistance amino-acid training studies pearance (AA) GH have (Ra)) 40 expanded metabolism, μg/d probably0.014 proteolysis evidenced μg/kg/min related protein with rates. synthesis in In reduced Rd general, PHe leucine acute GH to oxidation, suppress Locally insulin infusion increased infused proteolysis exerted GH an nonox- sti- anabolic effect on kept stable Fryberg to maintain the poolmore Garibotto ofcebo pearance more essential consistent (Ra)) consistent Brachial amino over than probably arterytrial than acids acute 6-week acute infusion mic (EAA) run riseinvolved administration related with 5locally administration mg notdosage. 3dosage. times ininapromoting Regarding week promoting BCAAs Regarding Rdan chronic an chronic increase increase GH hesis GH ininexposure,exposure, whole-body synthesis whole-body it seems and itpro- pro- seems fast[40] e Fryberg state;[47] man from7 an 7evolutionary healthy healthy GH/placebo 6 Dialysis Brachial malnourished The idative GH action point acute more +artery of of leucine insulin/no infusionGH for and consistent 12 on infusion patients view, of weeks disposal, 6-week pla- muscle GH than under To anon Totissue To rise acute haemodialysis amino rise amino-acid increased locally is for mainly acid locally Leu. not 6 administration Ox amino weeks.(AA) syste- anabolic [47]. metabolism not Ra metabolism, acid BCAAs BCAAsand strength results disappearance inreported promoting has little inand evidenced anGH a effect protein profound rate mulates increase tomulates on synt- suppress in (Rd) reduced decreased in proteolysis. reduction (all skeletal skeletal proteolysis indexes whole-body muscle negative in muscle leucine Still, oxidation, ofpro- muscle incre ion. 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RdOx GH strength that blunted acute andaction the GHprotein ofin infusion Fryberg emuscle conservationtissue isofmainly Author vital protein Subjects 7 anabolic healthy rate stores more and3 hof GH muscle [38]. consistent malnourished has Humans’ Design little proteins. then 3 than effect h patients By Insulin nitrogen acute on contrast, 0.02 pearance administration under proteolysis. GH (1) other mU/kg/min Dose (Ra)) basal haemodialysis Still, studies in 6 probably h promoting using Rd [47]. Effectshigher an suppression doses with increase of dosage.in GH Conclusions insulin found Regarding whole-body lower pro-chronic GH expos [40]different7 healthy malnourished increased GH +rates. patients whole-body insulin/no pla- under protein To haemodialysis rise(2) synthesis locally not [47]. Raany significant without syste- insulin hesis changes in the of synthetic balance, o [40] maintain the pool EAA of Table Table radiolabelling essential 1.1. 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Resistance demonstrated Resistance disposal, clamp/controlled training training patients that an increased systemic Table under acute GH 1GH GH 40 tients μg/d with 40infusion μg/d haemodialysis amino growth release [47]. hormone protein protein GHsynthesis synthesis deficiency rate Similar protein (Rd) (GHD) muscle synthesis. indexes size, [45,46], and after GH admi Author Author Subjects fasting amino-acid Subjects Design (AA) Design metabolism, 0.014 0.014 μg/kg/min μg/kg/min GH fasting evidenced GH Dose Dose+ SSAs inRd reduced Rd PHePHe Effectsleucine Effects oxidation, Locally Locally excretion strength infused increased and Conclusions infused Conclusions GHand GHproteinincreased sti- nonox- sti- synt- anabolic udies Fryberg and assessing [44] Fryberg has little protein effect anabolism manwithout on proteolysis. protein Brachial using Brachial synthesis) artery GH/placebo Still, and infusion radioisotopes. artery infusion less GH The effect 0.014 on μg/kg/min malnourished for 12synthetic weeks protein breakdown 3 patients h Rd Leu. 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(Ra)) and Brachial placebo onstudies artery higher thenprobably artery 3 h infusion proteolysis. with infusion doses GH of related Insulin GHStill, evaluating 0.02 found with dosage. mU/kg/min protein fasting lower with Regarding anabolism SSAs h Rd using radioisotopes. +BCAAs GH exposure, seems 77healthy 7 healthyhealthy protein synthesis) andsystemicless systemic To To effect rise riselocally locallynot on locally not protein not releasebreakdown release BCAAs (a insulin lower protein protein mulates rate mulates of synthesis. synthesis. amino skeletal skeletal muscle acid muscle ap- d[40] metabolism results in a profound +reduction in depending In[39] [39] on general, Author the acute infusionmore circumstances, GHSubjects GH no consistent dose exerted Brachial pearance Brachial noinsulin/no and placeboan time than placebo anabolic artery Design artery(Ra)) ofpla- Table infusion infusion acute exposition. effect probably To 1. GH GH on administration rise Most systemic relevant whole-body systemic 0.014 related 0.014 GH GH replacement. μg/kg/minwith Dose μg/kg/min syste- studies in promoting dosage. 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Some significant 77healthy studies healthy changes demonstrated tients in the with Brachial that synthetic growth artery acute infusion GH hormone infusion deficiency (GHD) and after Similar GH insulin insulin GH GH muscle administration blunted blunted Acipimox the size,the action in action increased of of whole sposal, Yarasheski [40] [40] Fryberg an Fryberg increased18 amino healthy 7 healthy acid disappearance Resistance GH3GH h GH tein + 3 insulin/no h GH + synthesis training insulin/no and andSubcutaneous rate pla- then pla- then [42–44]. 3h 3(Rd) GH To h To (all 40 rise rise indexes μg/d locally Insulin riselocally ToSimilar Insulin locally 0.02 GH 0.02not not ofsyste- mU/kg/min not syste- mU/kg/min results have replacement protein RaBCAAs 6Ra been 6 h synthesis h RdreportedRd 0.014 μg/kg/min after mulates GH Rd skeletal administration PHe muscle in pa- Locally infus er n studies Nielsen [39] synthesis using without higher 7 healthy any doses 7 healthysignificant 7 GHD of GH malnourished Fryberg found no changes placebo lower patients in the under synthetic haemodialysis Brachial artery [47]. infusion Leu. Ox Ra strength totosuppress insulin suppress insulin and body protein proteolysis proteolysis and forearmsynt- protein )[44] and less [40] [40] [46] effect on man protein breakdownGH/placebo cebo cebo GHtients GH (a + insulin/no with lower + insulin/no 7growth healthy GH/controlled rate pla- pla- of for mic amino 12 micrise systemic To hormone weeks To rise acid +/ locally ap- locally −not not (GHD) acipimox syste- BCAAs syste- BCAAs release Ra Ra[45,46], To Rd rise locally not GH protein BCAAs synthesis. in mulates skel nfusion other ontrast, exerted an anabolic studies using higher effect [39] on doses whole-bodyof GHinfusionfound lower no deficiency placebo and hesis after to suppress to suppress administration breakdown, proteolysis proteolysis and protein robably related with dosage. Regarding Brachial cebo cebochronic malnourished artery GH exposure, patients GH mic mic it 0.014 under seems μg/kg/min haemodialysis 3BCAAs h Rd [47]. BCAAs systemic Similar muscle Similarsynthesis musclerelease size, size, protein synt Yarasheski dacutein reduced Yarasheski GH infusion 18 leucine Table 18healthy 1. an oxidation, healthy exerted Most relevant Resistance increased anabolic Resistance studies nonox- onwith training training GHGH evaluating GH40 40μg/d μg/dprotein anabolism protein protein synthesis using radioisotopes. synthesis GH blunted the action of hanFrybergacute administration in promoting 3 h GHeffect an andincreasethen whole-body 3 h in whole-body Insulin Brachial 0.02 mU/kg/min pro-artery infusion 6 h RdGH 0.014 μg/kg/min strength strength Similar Similar andand muscle hprotein 3 muscleRd protein size, synt- size, synt- Leu. Ox Leu.protein synthesisinsulin mino,[44] [44]Yarasheski [40] acid disappearance Yarasheski evidenced –44]. Similar Author Shortin man 718 reduced results 18 healthy healthy man healthy have Subjects Table rate Fryberg leucine been (Rd) GH/placebo reported 1. Most (allResistance GH/placebo Resistance oxidation, GHrelevant indexes after Design + insulin/no training GH studies training Randomised increased of pla- forfor12 GH nonox- administration withTo GH 40weeks GH 12 rise GH 40 μg/d weeks μg/d 3 h GH locally evaluating GHinnot Dose pa- and (150 thenanabolism syste- proteing/h; protein 3Ra 2,1 Oxsynthesis h ± EffectsInsulinusing 0.02 hesis mU/kg/min hesis strength radioisotopes. After strength Conclusions and 6 hGH Rdsynthetic and protein protein synt-synt-rate of GH blunted [44] man GH/placebo 7 healthy for 12 weeks Leu. Leu. Ox Ra Ox to suppress proteolysis insulin otein [44] breakdown ncreased amino (a lower man acid 9rate disappearance healthyof cebo amino GH/placebo rateand acid (Rd) ap- crossover (all GH design indexes for 12 weeks micof hesis th hormone [43]deficiency (GHD)[40] [45,46], after GH/FS administration 0.014 GH0.1 μg/kg/min + insulin/no g/kg in h) Rd pla- BCAAs PHeTo Rd rise locallyLocally not hesis syste-infused muscle Ra proteins GH sti- to suppress p Fryberg osage. Regarding chronic GH Brachial artery infusion ffect tients on underAuthor 7breakdown protein healthy haemodialysis Subjects (aexposure, [47]. lower rateitof seems Design amino acid To rise ap- locally ceboGH not Dose BCAAsmic Effects mulates Similar skeletal muscleConclusions BCAAs muscle size, [39] Yarasheski no placebo training protein synthesis on ted in with Fryberg dosage.18 promoting an healthy increase chronic Regarding Resistance in whole-body GH exposure, Brachial pro- it systemic artery infusion GH0.014 seems 40 μg/d A 1-h iv infusion μg/kg/min release ofRd PHe protein strengthLocallyAdministration synthesis. and infused proteinGH ofsti- synt- GH Similar mus ve[44] been Buijs reported manafter 7 GH healthy 6 NW Yarasheski GH/placebo administration in 18 Crossover pa- healthy for 12 design To Resistance weeks rise SSAs locally and training not GH Leu.BCAAs (12 Ox GH 40 μg/d mulatesblunted protein the skeletal synthesis rise musclein Leu Ox dministration with GH [39] evaluating in promoting protein anabolism an increase Brachialusing no placeboin artery whole-body radioisotopes.infusion GH pro- 0.014 μg/kg/min 3 h Rd Leu Ox GH hesis strength and [41] 6 OB [44] man placebo GH/placebo mU/kg/h or for 12 weeks blunted similarlyLeu. the Ox action in both of NW and (GHD) results [45,46], rFryberg have been andreported after GH afteradministration 3 hGH and thenin GHadministration 3h systemic in pa- 0.02placebo Insulin mU/kg/min 6 h Rd release protein synthesis. hesis GH 7 healthy Dose Effects artery infusion Conclusions insulin OB ysis [40] [47]. (GHD) deficiency [45,46], and GH after+Brachialinsulin/no GH administration pla- To rise GH in locally0.014 μg/kg/min not syste- Ra 3 h Rd GH blunted the action of 0.014 μg/kg/min Fryberg Rd ceboPHe3 h GH Open-label and then Locally 3 hmic infusedInsulin GH0.02 sti-mU/kg/min 6 h Rd to suppress No effectproteolysis in protein haemodialysis nfusion [47].7 healthy BCAAs insulin [40] in anabolism Gibney To rise locally using not 12 hypopit. radioisotopes. randomised BCAAs GH + insulin/no mulates pla- skeletal To risemuscle locally not syste- Ra breakdown, suppressing 0.5 mg daily 6 weeks Similar muscle size, to suppress proteolysis Yarasheski [42] 18 healthy man systemic Resistance release cebo crossover training protein GH 40 μg/d synthesis. mic protein synthesis BCAAs protein ox and stimulating uating proteinEffects anabolism using radioisotopes. Conclusions testosterone forand12GH strength and protein synt- protein synthesis [44] GH 0.014 μg/kg/min nfusion man 3 h GH/placebo Rd weeks Leu. Ox Similar muscle size, GH bluntedGH the40 action μg/dof protein synthesishesis h Yarasheski 3 GH Rd Dose PHeAdapted Insulin 18from: healthy 0.02 mU/kg/min Locally Effects Jørgensen Resistance 6 h infused RdJOL, sti- training GHConclusions Christiansen JS. Growth Hormone Deficiency in Adults. Book. Karger Medical and Sci-entific strength Publishers; and protein synt- [44] BCAAs man mulates GH/placebo skeletal muscle insulin for 12 weeks Leu. Ox pla- μg/kg/minTo rise locally not 2005.Rd PHe syste- Decrease Ra Locally infused Increase, GH sti- not change. Ins: insulin, Leu: leucine, Ox: oxidation, BCAAs: hesis branched-chain amino acids, Phe: to suppress proteolysis e locallyrelease mic BCAAs protein not phenylalanine, NW:BCAAssynthesis. normal mulates skeletal weight, OB: obese,muscle wk week. Units: Kg: kilogram, h: hours, IU: international units, min: minutes, mg: min mic 3 h Rd milligram, releasemU: primary units, µg: microgram. protein synthesis. Rd: (Phe/Leu Similar disappearance rate) represents protein synthesis. Ra: (rate of appearance of muscle size, ng GH 40 μg/d GH blunted Phe/Leu) represents protein the action synthesis proteolysis. Hypopit:of hypopituitarism. Ox—oxidation. g/min 6 h 014 μg/kg/minRd 3 h Rd insulin strength and protein synt- for 12 weeks Leu. OxGH blunted the action of nsyste- Ra 0.02 mU/kg/min 6 h Rd to suppress proteolysis hesis insulin Norreland et al. (2001) [48] evaluated the action of GH on fasting longer than overnight. e locallyBCAAs not syste- Ra to suppress proteolysis BCAAs Similar muscleThey protein synthesis size, found that GH suppression led to increased proteolysis and with GH replacement strength andSimilar protein synt- they muscle found size, a significant decrease in branched-chain amino acid levels, consistent with 0 μg/d Leu. Ox protein synthesis hesis decreased proteolysis. strength and protein synt- weeks Leu. Ox hesis Nevertheless, in studies designed to recover the muscle loss in the elderly, the over- all impact of GH administration has been far lower than expected [44,49,50]. Little is known about GH uses in fitness [51]. However, recently, in patients in need of reparative knee surgery Mendias et al. (2020) [52] found that rhGH compared to placebo improved quadriceps strength and reduced MMP3 (a subrogated marker of cartilage degradation). lipids. knowledge regarding the relationship between skeletal muscle and me and lipid metabolism Furthermore, thereandwas musclea shift composition toward biopsied in 19insulin-resistant GH-deficient muscles during adultGH subjects. II Xtherapy. GHinther- These studies significant type more composition. However,type whether fibres this muscular the fibre shift represents (9.6 apy μg/kg resulted biopsied body in muscles weight/d) glucose during GH metabolism GH replacement deterioration therapy. therapy knowledge These and or an placebo enhanced regarding studies on the significantly whole-body lipid oxidation relationshipincreased glucose rate between in our skeletal muscle and m consequence (9.6 μg/kg body weight/d) GH replacement therapy or placebo on whole-body glucose of insulin resistance requires further investigation. and both lipid short knowledge metabolism and long-term regardingand and muscle treatment themuscle relationshipcomposition groups, type between in 19 reflecting GH-deficient composition. skeletal a fuel use However, muscle adult adult switch subjects. from whether and metabolism’s GH glucose this ther- to muscular fibre shift fibre to ageing. In particular represen and lipid metabolism composition Moreover, in 19 GH/IGF1 GH-deficient levels have been subjects. GHrelatedther- apy resulted lipids. typeresulted composition. in glucose However,metabolism whether deterioration this consequence muscular and an fibre ofenhanced insulin shift lipid resistance represents oxidation requires the cause rate in further or the investigation. apy Int. J. Mol. Sci. 2021, 22, short 415 in glucose metabolism tion deterioration by theand skeletal muscle an enhanced is impaired lipid oxidation in older rate humans and7linked in of 18 with a both consequence andoflong-term Furthermore, insulin treatment thereresistance was a shift groups, towardfurther requires reflecting more a fuel insulin-resistant Moreover, investigation. GH/IGF1use switch type levelsII from glucose X fibres have beeninrelated to the to ageing. In particu both short and long-term treatment copenia groups, [30]. Therefore, reflecting a fuel use GH/IGF-1 switch from actions glucose in the to muscle have structural lipids. biopsied muscles during GH therapy.tion These by the studies ageing.significantly skeletal muscle is impaired increased IGF-1 in olderour humans and linked with lipids.Moreover, GH/IGF1 levels have been ageing related to consequences In and particular, vice versa. produc- Furthermore, knowledge tion Furthermore, regarding by the skeletalthere there musclethewas a shift relationship toward between more copenia insulin-resistant skeletal [30]. muscle Therefore, andtype II X metabolism’s GH/IGF-1 fibres actions in the fibre in the muscle have structur wasis aimpaired shift toward in older more humans and linkedtype insulin-resistant with IIaged related X fibres in sar- the biopsied type copenia [30]. muscles composition. Therefore, during However, GH GH/IGF-1whether therapy. this actions These muscular ageing in studies fibre consequences shift significantly represents and vice increased the versa. cause or our the biopsied muscles Altogether, during GH these therapy. experiments GHthe muscle 4.1. These support studies have structural, the anabolic significantly metabolic action increased of GHour and with less effect on knowledge consequence ageing regarding consequences of proteolysis, insulin the and relationship resistance vice versa. depending requires between on further time skeletal investigation. length andmusclethe and metabolism’s context of GH fibre These effects exposition. knowledge regarding the relationship between The skeletal first reportsmuscle on and the metabolism’s anabolic growth fibre type composition. Moreover, probably However, GH/IGF1 becomewhether levels have more this been 4.1. muscular evidentrelatedGH with tofibre shift ageing. more Inrepresents prolongedparticular, GH the cause IGF-1 exposure orhormone produc-orthe effects dated back t in a pathological type composition. consequence of insulin However, whether this muscular gested that fibre GH shift inhibits represents proteolysis the cause during or fasting the [35]. Subsequent studies tion 4.1. GHby the skeletal consequence of insulin asresistance statemuscle is impaired acromegaly resistance requires accompanied requires further in older further investigation. humans The by first and linked reports elevated investigation. on the insulin with aged IGF-Irelated anabolic and levels.sar- growth hormone effects dated bac copeniaMoreover, GH/IGF1 GH/IGF-1 [30]. Therefore, levels haveactions been thisrelated concept in thethat to [36,37]. ageing. muscle have In particular, structural, IGF-1 metabolic produc- and [35]. Subsequent stud The first reports on the anabolic growth gested hormone GH inhibits effects dated proteolysis back toin during 1948 and fasting sug- Moreover, GH/IGF1 4.2.muscle IGF-1 levels have been related GH is totheageing. primary In particular, hormone IGF-1the produc- fast sar-state; from an evolutionary tion ageingby the skeletal consequences and vice is impaired versa. in older this humans concept and [36,37]. linked with aged related gested tion by that GH inhibits the skeletal muscle proteolysis is impaired during inwhen fasting older [35]. humans food is Subsequent and linked scarce, GH studies with aged changes have fuel expanded related consumption sar- from carbohydrates an copenia [30]. Therefore, IGF-1 GH/IGF-1 is one of actionsthe mostinimportant the GHmuscle is the have primary signals structural, in hormone muscle metabolic anabolismin the and andrepairs fast state; from an evolutiona [30,53,54]. this concept copenia [30]. [36,37]. Therefore, GH/IGF-1 actions usein of thelipids,muscle have for allowing structural, the conservation metabolicofand vital protein stores [38]. Hu 4.1. GHconsequences ageing As and mentioned vice versa. above, IGF-1 is secreted by the liver after GH stimuli ageing GH is the primary consequences andhormone vice versa. in thebalance when fast state; food mustfrom is scarce, be kept GH an evolutionary changes stable to maintain fuel pointthe view,of essentialfrom consumption of pool and directly from carbohydrates amino acids The first skeletal reports on muscle the when food is scarce, GH changes fuel consumption in anabolic an autocrine/paracrine growth use hormone of lipids, from manner effects allowing dated carbohydrates [33]. for back theIGF-1 to mediates 1948 conservation and protein and to beneficial sug- of the outcomes vital protein stores [38]. 4.1. GHthat GH inhibits in protein formation. Considering this balance, different EAA radiolabel gested useGH of physical of lipids, allowing for the conservation activity proteolysis [55] during and can fasting balance prevent [35]. must chronic Subsequent be kept disease stablestudiesto [56].have maintain expanded the pool of essential amino acid 4.1. haveofbeen vitalused protein stores [38]. to evaluate theHumans’ effects ofnitrogen GH and IGF-1 on protein meta this balanceThe concept first reports [36,37]. The on first the reports anabolic of IGF-1 growth inpool date hormone protein back to 1957 effects formation. as dated “sulphation back Considering to 1948factor”, and thisinvolved when sug- Salomon balance, different EAA et al. radiolab The must be kepton first reports described stable the its to maintain anabolic ability togrowth the summarises stimulate hormone of essential the 35-sulphate results effects amino dated incorporation acidsto(EAA) of studies back assessing 1948 into protein anabolism using rad andcartilage. rat sug- Later, IGF-1 gested GH in proteinthatisGH theinhibits formation.primary proteolysis hormone during Considering in this fasting thebalance, fast havestate; [35]. been fromSubsequent used anto evolutionary evaluate studies thehave point effects expanded of of view, GH and IGF-1 on protein m gested that GH inhibits proteolysis during action fasting of different GH [35].on EAA muscle Subsequent radiolabelling tissue studies is mainly have techniques anabolic and has little effect on p expanded this when concept food haveconcept been used is (called [36,37]. scarce, GH somatomedin-C) changes to evaluate the effects of fuel was consumption assumed summarises from to the be a carbohydrates results mediator of and studies of anabolic protein assessing to and the 1 mitogenic protein anabolismGH using r this [36,37]. theGH effects andcould IGF-1beon proteindepending different metabolism. onTable the circumstances, dose and tim use GH of summarises is lipids, the the activity primary allowing results [57], forhormone of the but thisin conservation studies concept the assessing fast of action drastically state; vital protein of from protein GH changed on an anabolism stores muscle after evolutionary [38]. usingtissue verification Humans’ is point mainly radioisotopes. of of nitrogenthe view, anabolic The localandproduction has little effect on when GHfood is isthe primary and scarce, action GH hormone oftoIGF-1 changes fuel theThe in[33,58]. fastacute consumption state;infusion from anofevolutionary fromcarbohydrates GH on amino and pointacidofmetabolism protein view, to the results in a profou balance actionfood must of GH be kept on muscle stable maintain tissue is fuel mainly the the anabolicpool effectsofand essential could has be amino different acids little[36,37,39–41]. effect onand (EAA) depending proteolysis. involved on the Still, circumstances, dose and when is scarce, GH changes Immediately after amino consumption IGF-1 acid biosynthesisoxidation from carbohydrates [59], a new challenge Someinstudies protein to the demonstrated clinical research was that acu use in of theproteinlipids, effects could allowing formation. for thedepending Considering be different conservation this balance, onThe of vital the acute protein differentinfusion circumstances, stores EAA [38]. onHumans’ ofradiolabelling dose GH and amino time nitrogen of techniques acid exposition. metabolism results in a profo use of lipids, allowing opened for up.the conservation First, Guler et increased al. of(1987) vital whole-body protein [60] comparedstores protein [38]. eight synthesis Humans’ healthy without nitrogen adult any significant volunteers, the short-changes balance have The been acute must used be infusion kept to of stable evaluate GH to on themaintain effects amino acid the of GH pool amino metabolism andof acid essential IGF-1 on oxidation results amino protein in a acids (EAA) metabolism. [36,37,39–41]. profound involved Some reduction Table studies in1 demonstrated that a balance must beterm kept metabolic stable to maintain effects ofrate theIFG-1 of pooland muscle of essential proteins. insulin. By aminoLaron Next, contrast, acids et (EAA) other studies involved al. techniques (1990) [61,62] using higher doses of G investigated in protein summarises amino formation. the acidformation. results Considering oxidationConsidering of studies [36,37,39–41]. this assessing Somebalance, increased studies different protein whole-body demonstratedEAA anabolism radiolabelling using protein that radioisotopes. acutesynthesis GH infusion The without any significant chang in protein this proteolysis balance, rates. and different In EAA general, acute radiolabelling GH infusion techniques exerted an anabolic effect have action been increased of GH used onIGF-1 whole-body to muscle impact evaluate tissue protein oniseffects the GHRH mainlyof synthesis in healthy GH anabolic rate without and adults and of muscle anyIGF-1 on hasproteins. little significant children protein effect changes with Bymetabolism. on primary proteolysis. contrast,in the other TableIGF-1 syntheticStill,1 deficiency studies (GH doses using higher o have been used to evaluate insensitivity) theor effects Laron’s amino-acid of GHprotein Syndrome and IGF-1 (AA) (LS). metabolism, on Laron protein et al. evidenced metabolism. were also thein Table reduced first leucine oxidation, 1to introduce the in summarises the effects rate of muscle the could results be of different studies depending assessing on the anabolism circumstances, proteolysis rates. In dose using general, and radioisotopes. time acute ofGH exposition. infusion The exerted an anabolic effe summarises theproteins. results ofBystudies contrast, other assessing idativestudies protein using leucine higher using disposal, anabolism doses anLS of increasedGH found radioisotopes. aminolower acid The disappearance rate (Rd action The of GH acute proteolysis onlong infusion rates. muscle In ofterm GH general, administration tissue onacuteis mainly amino GH acid of anabolic biosynthetic metabolism amino-acid infusion and has exerted IGF-1 little results (AA)an in anabolic in effect on a profound metabolism, [63,64]. effect proteolysis. evidenced on Some reduction whole-body of Still, in the in mostleucine reduced relevant oxidation, action of GH onstudies musclein tissue humans, is mainlywith protein anabolic systemic synthesis) and IGF-1 has and little administration less effect effect on on protein proteolysis. and of its impact breakdown Still, on protein and the rate (a lower of the aminoeffects amino-acid acid could(AA) bemetabolism, oxidation different depending [36,37,39–41]. evidenced Some on the studies idative in circumstances, reduced demonstrated leucine leucine dose disposal, and that oxidation, time acute an increased increased GHexposition. infusion amino nonox- acid disappearance rate (R the effects couldmuscular be different depending system, pearance on the circumstances, is summarised (Ra)) in Table probably 2. and related with dose and time of exposition. dosage. Regarding chronic GH exp The acute increased idative infusion whole-body leucine of GH disposal, proteinonincreased amino synthesis acid metabolism without protein any results significant synthesis) in achanges profound less (Rd)in(all effect reduction theindexes on synthetic protein inbreakdown (a lower rate The acute infusion of GHan on amino acid amino more acid consistent metabolism disappearance than in results acute a rate administration profound reduction of in promoting in an increase in w amino rate of proteinacidacid muscle oxidation synthesis) proteins.and [36,37,39–41]. By contrast, less effect Some other studies pearance demonstrated using (Ra)) higher probably that doses acute of related GH GH found with infusion lower dosage. Regarding chronic GH e amino Table oxidation 2. Most studieson [36,37,39–41]. relevant protein Some in teinstudies humans, breakdown synthesis with demonstrated systemic (aIGF-1 [42–44]. lowerSimilar that and rate of amino results acute muscle GH have actions. acidbeen infusion ap-reported after GH admin increased proteolysis whole-body pearance whole-body rates. (Ra)) probably In protein general, related synthesis acute GH with dosage. without infusion more any exerted consistent Regarding significant an anabolic than chronic changes acute effect GHdeficiency inon the administration exposure, synthetic whole-body in promoting it seems[45,46], and after an increase in increased protein synthesis tients without with any growth significant hormone changes (GHD) in the synthetic GH ad rate more of consistent amino-acid muscle (AA) proteins. than By contrast, metabolism, acute evidenced administration other in studies teininreduced using synthesis promoting higher leucine [42–44]. Muscle an doses oxidation, increaseSimilar of in GH increased results found Muscle whole-body have lower nonox- been reported after GH adm pro- Author rate of muscle proteins. Subjects DesignBy contrast, other malnourished patients under studies using higher doses of GH found lowerConclusions haemodialysis [47]. proteolysis idative leucine tein synthesis rates. In [42–44]. general, disposal, Similar acute an increased resultsGH Dose infusion amino tients acidexerted with an disappearance growth anabolic Anabolism hormonerateeffect (Rd) on whole-body (all deficiency Function indexes (GHD) of [45,46], and after GH proteolysis rates. In general, acute GH have infusion been reported exerted an after anabolic GH administration effect on whole-body in pa- amino-acid protein tients with (AA) (AA) synthesis) growth metabolism, and less hormoneTable evidenced effect on deficiency rhGH: protein 1. Most0.05inin (GHD) reduced mg/kg relevant breakdown malnourished [45,46], studies leucine With (a and IGF-1 with oxidation, lower patients after GH rate under serum evaluating increased of amino haemodialysis GH increased administration nonox- acid protein nonox- anabolismap- [47]. in using radioisotopes. amino-acid metabolism, 2 weeksan evidenced reduced leucine oxidation, IGF-1 idative pearance malnourishedleucine disposal, (Ra))patients probably increased related under d oramino *6with haemodialysis dosage. iv infusion acid disappearance Regarding [47]. ureachronic nitrogen rate GH(Rd) exposure,(all indexesit seems of reversed the Clemmons idative leucineAuthor disposal, caloricallyan increased Subjects 1.amino acid Design disappearance rate (Rd) (all indexes of catabolism caused protein more synthesis) consistent 6 healthy thanandacuteless effect Table on protein administration Most of in relevant breakdown promoting studies anwith (a the reduction lower GH increase rate was inGH evaluating Dose ofwhole-body amino NAprotein acidanabolism ap- pro- Effects using radioisotopes. Co [65] protein synthesis)restricted and less effectrhIGF-I on protein breakdown (a lower rate of amino acid ap- by a restriction Table 1. Most pearance tein synthesis relevant (Ra)) studies probably [42–44]. with GH related Similar evaluating with results 12 dosage. µg/kg haveBrachial protein been anabolismRegarding reported greater using than chronic after GH 0.014 with radioisotopes. GH μg/kg/min exposure, administration it seems Rd PHe in pa- of theEffects Locally in pearance (Ra)) Fryberg Author probably related Subjects with dosage. artery Regarding Design infusion chronic GH GH Dose exposure, it seems diet. more tientsconsistent with[39] growth thanhormone 7 healthy acute administration IBW deficiency (GHD) *16 h inplacebo promoting [45,46], and GH an increase To after0.014rise GH locally in μg/kg/min not whole-body pro- administration BCAAs inRd PHe mulates s no Locall thor Subjects more consistent Design Fryberg than Acuteacute administration GH Dose IGF-I doses in promoting Brachial Effects artery an increase infusion systemic in whole-body Conclusions pro- release protein s tein synthesis [42–44]. malnourished patients Similar under results haemodialysis 7 healthy have been [47].reported after GHToadministration rise locally in pa-BCAAs Turkalj tein synthesis[39] 19 Brachial healthy [42–44]. randomised Similar 0.014 results μg/kg/min have 5, 7.5, 15 been no Rd Brachial and reported PHe artery placebo Dose-dependent after GH infusion GH Locally infusednot administration 0.014administration μg/kg/min GHin sti-pa- 3inh Rd GF-1 proteolysis mulate g tients withartery growth hormone deficiency infusion (GHD) [45,46], and decrease after GH systemic release GHprotein blun 7 healthy [66] 1. Most tients manwithstudies growth Fryberg hormone rhIGF-1 To risedeficiency locally 30 not (GHD) 3anabolism h GH BCAAs [45,46], thenand 3 h after mulates GH 0.02 skeletal NA muscle6inhIGF-1 administration Rd protein Table relevant malnourished no placebo with patients GHunder evaluating haemodialysis 7 healthy µg/kg/h protein [47]. andartery Brachial using Insulin ofradioisotopes. leucine GH 0.014 μg/kg/min infusion mU/kg/min 3 h Rd insulin malnourished [40] ascending patients under systemic doses (n = 4) andGH haemodialysis saline +release [47]. pla- Toprotein insulin/nooxidation. rise locallysynthesis. not syste- Rasynthesis GH bl thor Subjects Fryberg vs. saline. control Dose (ncebo= 33). h3GH and then 3 h micInsulinConclusions 0.02 mU/kg/min 6 h Rd to suppre BrachialDesign artery infusion GH 70.014 GH μg/kg/min healthy h Rd Effects BCAAs insulin Table 1. Most relevant studies [40] with GH evaluating protein anabolism GH + using radioisotopes. insulin/no pla- GH To blunted rise thenot locally action syste-of Ra g 3 h GH studies Table 1. Most relevant and then 3 h GH0.014 with Insulin μg/kg/min 0.02 protein evaluating mU/kg/min Rd 6 h PHe anabolism IGF-1 Locally Rdusing radioisotopes. infused GH sti- Similar to supm g 7 healthy Brachial Yarasheski artery infusion 18 healthy insulin thor 7 healthy Subjects 5 healthy DesignRandom GH + insulin/no pla- order of GH To rise 3-hDose locally IVnot Resistance infusioncebo syste- of BCAAs Ra training Effects RaGH 40 μg/d mic mulates skeletal muscleprotein Conclusions BCAAs IGF-1 synthesis increases strength thor Subjects no placebo adequate [44] Design both IGF-1 man GH or μg/kg/min Dose GH/placebo IGF-1: 43.7 Rd Effects forto12suppress weeks proteolysis Conclusions Leu. Ox Simila Russell- cebo Yarasheski systemic mic 0.014 18 healthy release BCAAs protein PHe trainingRd Locally Resistance GH 40 infused μg/d GH sti-protein synthesis. synthesis in protein synthesis hesis Jones Brachial artery substrate infusion insulin 0.014 1 week μg/kg/min pmol*kg/min Rd or PHe Locally infused NA GH sti- contrast to insulin, streng 7 healthy Brachial Brachial artery artery [44] infusion infusion GH To 0.014 rise man μg/kg/min locally not 3 h BCAAs Rd GH/placebo Insulin GHmulates Similar for 12 skeletal muscle muscle size, Leu. Ox weeksthe action of which eski 718 healthy [67] healthy no placebo Resistance supply training apart + AA GHrise To 40 locally μg/d Insulin protein synthesis mulates not 3.4 release BCAAs blunted skeletal muscle acts to hesis g 3 hplacebo no GH and then 3 h systemic Insulin 0.02 mU/kg/min 6 h Rd Ra protein strength synthesis. and protein synt- 7man healthy condition), GH/placebo infusion for 12 weeks systemic pmol/kg/minreleaseLeu. Ox insulin synthesis. protein reduce proteolysis. GH + insulin/no Brachial pla- GH artery infusion To rise 0.014locally not syste- 3Ra μg/kg/min h Rd Rd to hesis Brachial artery infusion GH 0.014 μg/kg/min 3 h Rd GHsuppress proteolysis blunted the action of cebo 3 h GH and then 3 h mic Insulin 0.02 mU/kg/min 6 h Rd BCAAs GH blunted the action of 7 healthy 3 h GH and thenpla- 3h Insulin IV infusion 0.02 mU/kg/min of6 h Rd insulin 718healthy GH + insulin/no 2 weeks To rise locally not 12 rhIGF-1 syste- µg/kgRa Similar muscle size, Combination of GH insulin eski healthy Resistance GH + training insulin/no pla- GHrise To 40 locally μg/d not syste- protein synthesis to Ra suppress proteolysis cebo mic calorically IBW *16 h *5 dBCAAs strength to suppress and protein synt-and IGF-I was proteolysis man GH/placebo cebo for mic 12 weeks Leu. Ox BCAAsNitrogen retention Kupfer restricted or hesis Similar muscle size, substantially more ski 18 healthy 7 Resistance healthy training GH 40 μg/d proteinwassynthesis 2.4-fold greater Similar muscle NAsize, ski 18 [68] healthy Resistance (20 kcal/kgGH training IBW 40 μg/d rhIGF-1 (sameprotein synthesis strength and protein synt- anabolic man GH/placebo for 12 weeks Leu. Ox in combination strength and protein synt- man GH/placebo per d), with for1 12 g weeks doses above) +Leu. Ox hesis than either GH or protein/kg IBW. rhGH: 0.05 mg/kg hesis IGF-I alone. *5 d protein pearancesynthesis) and less (Ra)) probably effectwith related on protein dosage.breakdown Regarding (a lower GH chronic rate exposure, of amino it acid ap- seems pearance (Ra)) probably related with dosage. Regarding chronic GH exposure, more consistent than acute administration in promoting an increase in whole-body pro- it seems more consistent tein synthesis than acute [42–44]. administration Similar results have in promoting been reportedan increase after in whole-bodyinpro- GH administration pa- tein tientssynthesis [42–44]. with growth Similardeficiency hormone results have been reported (GHD) after [45,46], and GHGH after administration in pa- administration in tients with growth malnourished Int. J. Mol. Sci. 2021, 22, 415 hormone patients deficiency (GHD) under haemodialysis [47].[45,46], and after GH administration in 8 of 18 malnourished patients under haemodialysis [47]. Table 1. Most relevant studies with GH evaluating protein anabolism using radioisotopes. Table 1. Most relevant studies with GH evaluating protein anabolism using radioisotopes. thor Subjects Design GH DoseTable 2. Cont. Effects Conclusions hor Subjects Design GH Dose 0.014 μg/kg/min Rd PHeEffects LocallyConclusions infused GH sti- Brachial artery infusion 7 healthy To rise 0.014 locallyHigh μg/kg/min not doses RdBCAAs PHe mulatesinfused Locally skeletalGHmuscle sti- High doses of no placebo Brachial artery infusion (30 µg/kg/h IGF-I Ra 7 healthy systemic To rise locally not release BCAAs protein mulates synthesis. skeletal muscle no placebo Randomised and Rd IGF-1 compared to Brachial artery paired infusion GH 0.014or systemic three 0.23 nmol/kg/h μg/kg/min release 3 h Rd protein synthesis. Lagger 24 healthy insulin); ———— GH blunted the action ofinsulin decreased 3 h GH and Brachial then artery 3groups h infusion Insulin GH 0.0140.02 mU/kg/min 36 h Rd μg/kg/min Any change NA more proteolysis. 7 healthy [69] male low doses insulin GH blunted the action of 3GHh GH IGF-1-insulin + insulin/no and then pla- 3h To rise locally Insulin not syste- 6Rah Rd compared to 0.02 mU/kg/min Unexpected 7 healthy (5 µg/kg/h IGF-I to suppress proteolysis insulin cebo+ insulin/no pla- To GH micrise locally not syste- BCAAs Ra control inhibition of or 0.04 nmol/kg/h to suppress proteolysis protein synthesis cebo mic BCAAs Similar muscle size, ski 18 healthy Resistance training GH 40 μg/d insulin) protein synthesis strengthmuscle Similar and protein size, synt- ski man 18 healthy GH/placebo Resistance training for 12 GH 40weeks μg/d Leu. Oxsynthesis protein Boys with DMD. 6 hesis strength Didprotein and not synt- man GH/placebo for 12 weeks Leu. Ox months of rhIGF-1 Boys with Randomised, GC-treated + IGF-1 hesis observe a therapy did not Rutter DMD rhIGF-1 vs. (n = 17) vs. controls change in NA change motor [70] 21 control placebo. (GC-therapy only n functional function but did 17 IGF1 6 month = 21) motor improve linear outcomes growth. rhIGF-I/rhIGFBP-3 administration for Low dose Significant 28 days improved Randomised, rhIGF-I/rhIGFBP-3 increase in Nishan Fifty-six aerobic double-blind, (30 mg/d), or high maximal Guha recreational NA performance in placebo- dose oxygen con- [71] athletes recreational controlled rhIGF-I/rhIGFBP-3 sumption athletes, with no (60 mg/d) for 28 d effects on body composition. DMD = Duchenne muscular dystrophy EA: essential amino acid IBW: ideal body weight. Ins: insulin, Leu: leucine, Ox: oxidation, BCAAs: branched-chain amino acids, Phe: phenylalanine, wk week. NA: not available. (*) during. Units: d. day, kg: kilogram, h: hours, IU: international units, min: minutes, mg: milligram, mU: primary units, µg: microgram nmol: nanomole pmol: picomole, Rd: (Phe/Leu disappearance rate or nonoxidative AA disposal) represents protein synthesis. Ra: (rate of appearance of Phe/Leu) represents proteolysis. In healthy people, Clemmons et al. (1992) [65] found evidence that short term IGF-1 infusion, was able to reverse fasting diet-induced muscular catabolism. There is also some evidence indicating that the effects of the systemic administration of IGF-I on protein metabolism depend on environmental AA levels. In this regard, Turkalj et al. (1992) [66] showed that IGF-I administered without AA, suppressed proteolysis, while in the study by Russell-Jones DL, et al. (1994) [67]. IGF-1 administration in combination with AA infusion increased protein synthesis. Likewise, Kupfer et al. (1993) [68] found that GH and IGF-1 anabolic effects were enhanced when co-administered in 7 healthy calorically restricted patients. Lagger et al. (1993) [69], compared high and low doses of rhIGF-1 and found that high doses of IGF-1 decreased proteolysis more than insulin. However, it was accompanied by an unexpected inhibition of protein synthesis. More recently, some researchers have studied the effects of rhIGF-1 on muscle perfor- mance in special populations. Rutter et al. (2020) [70] investigated 21 boys with Duchenne muscular dystrophy and found that after 6 months of rhIGF-1 therapy, despite improve- ments in linear growth, muscular motor function did not change. Guha et al. (2020) [71] studied fifty-six recreational athletes and observed that muscular aerobic performance improved after 28 days of rhIGF-1/rhIGFBP-3 administration, but no effects on body com- position. It should be taken into account that circulating IGF-1 is probably less important in those tissues that can produce the hormone themselves, such as skeletal muscle [72] Focusing on ACRO, some degree of IGF-I receptor resistance to IGF1 action has recently been reported [73]. This important finding could explain why in the presence of high IGF1 levels, the metabolic GH effects are predominant in these patients. In addition, IGF-1 resistance might also be involved in other ACRO related muscle disturbances. In summary, these data suggest that the administration of IGF-1 inhibits proteolysis and improves muscle performance with less effect on protein synthesis. Other factors such as local IGF-1 secretion and/or IGF1R resistance could play an important role. The data is Int. J. Mol. Sci. 2021, 22, 415 9 of 18 ol. Sci. 2021, 22, x FOR PEER REVIEW 9 of 18 still controversial, and the combined and additive effect of IGF-1 and GH co-administration remains a subject of debate. 5. The in 5. The Key of mTOR Key of mTOR Muscle in Muscle Structural and Structural Metabolic and Metabolic Function Function Skeletal muscle mass and whole-body metabolism Skeletal muscle mass and whole‐body metabolism are closely related. are closely One of therelated. ma‐ One of the major playersgrowth jor players in coordinating in coordinating growth with nutrient with nutrient availability availability mammalian is rapamycin’s is rapamycin’s mammalian target (mTOR) [74]. There are two different mTOR complexes, target (mTOR) [74]. There are two different mTOR complexes, mTORC1 and mTORC2. mTORC1 In and mTORC2. brief, mTORC1 senses nutrients, oxygen, energy, and growth factors promote cell growth, promote cell In brief, mTORC1 senses nutrients, oxygen, energy, and growth factors growth, regulates metabolic regulates processes, metabolic and mTORC2 processes, respondsand mTORC2 more responds specifically more factors to growth specifically to growth and regulates cell survival and metabolism [75]. Specifically, mTORC1 plays a key rolemTORC1 factors and regulates cell survival and metabolism [75]. Specifically, in plays a key role in muscle structure, stimulating postprandial and post-exercise muscle structure, stimulating postprandial and post‐exercise muscle protein synthesis. muscle protein synthesis. This pathway is mainly activated by mechanical contraction (i.e., exercise), This pathway is mainly activated by mechanical contraction (i.e., exercise), which causes which causes paracrine IGF-1 secretion [72]. However, AA intake also participates in paracrine IGF‐1 secretion [72]. However, AA intake also participates in governing the governing the mTORC1 pathway. It has been shown that leucine is a potent stimulator of mTORC1 pathway. It has been shown that leucine is a potent stimulator of muscle protein muscle protein synthesis by triggering mTORC1 signalling in human skeletal muscle [76]. synthesis by triggering mTORC1 signalling in human skeletal muscle [76]. Recent work Recent work has found that during AA sufficiency, mTORC1 kinase activity is stimulated has found that during AA sufficiency, mTORC1 kinase activity is stimulated mainly in 3 mainly in 3 ways: (1) The lysosomal AA transporter SLC38A9 sensing arginine within the ways: (1) The lysosomal AA transporter SLC38A9 sensing arginine within the lysosome lysosome [77]; (2) The leucine sensor Sestrin2 [78]; (3) The arginine sensor [cellular arginine [77]; (2) The leucine sensor Sestrin2 [78]; (3) The arginine sensor [cellular arginine sensor sensor for mTORC1 (CASTOR1)] [79]. All these pathways ultimately allow mTORC1 to be for mTORC1 (CASTOR1)] [79]. All these pathways ultimately allow mTORC1 to be acti‐ activated (Figure 3). vated (Figure 3). Figure Figure 3. The 3. The of interplay interplay of GH, GH, IGF-1, IGF‐1,hybrid insulin, insulin,receptor hybrid receptor and nutrients and nutrients in the muscle. in the muscle. Sche‐and simplified Schematic matic and simplified signalling pathway and the interplay of GH, IGF‐1, insulin, hybrid receptor signalling pathway and the interplay of GH, IGF-1, insulin, hybrid receptor and nutrients in the muscle. AA (amino-acid) and nutrients in the muscle. AA (amino‐acid) stimulates mTOR kinase activity mainly in 3 ways: stimulates mTOR kinase activity mainly in 3 ways: (1) The leucine sensor Sestrin, (2) the lysosomal sensor SLC38A9, (1) The leucine sensor Sestrin, (2) the lysosomal sensor SLC38A9, (3) The arginine sensor [cellular (3) The arginine sensor arginine [cellular sensor arginine(CASTOR1)]. for mTORC1 sensor for mTORC1 (CASTOR1)]. GH activates GHSHC via IRIS and activates viaand protein IRISmitogenic and SHC protein and mitogenic effects as well as IGF-1R/InsulinR and HybridR. GH also stimulates via JAK/STAT effects as well as IGF‐1R/InsulinR and HybridR. GH also stimulates via JAK/STAT local muscular local muscular IGF-1 secretion. In addition, the metabolic effects of GH impact on muscle anabolism. The main IGF‐1 secretion. In addition, the metabolic effects of GH impact on muscle anabolism. The mainmetabolic action of GH is a lipolytic action on adipose metabolic actiontissue, of GHreleasing free action is a lipolytic fatty acids (FFA), which on adipose tissue, favours protein releasing preservation, free fatty as well as liver and acids (FFA), which favours kidney-enhanced protein preservation, as well as liver and kidney‐enhanced gluconeogenesis. gluconeogenesis. Similarly Similarly to IGF‐1R to IGF-1R resistance resistance described described in ACRO, in ACRO, an “anabolic an “anabolic resistance” due toresistance” an due to impairment of antheimpairment of the of “sensor” capacity “sensor” capacity the muscle of the muscle to metabolise to metabolise circulating circulating AA has AA has been been related related to the sarcopenia thattooccurs the sarcopenia that [76]. in the elderly occurs in reduced This the elderly [76]. ability This reduced ability is is probably associated with probably associated impairments with impairments in molecular signallingin such molecular signallingamino as decreased such as decreased amino acid acid transport, which results in reduced transport, which results in reduced mTORC activation. mTORC activation. Recently, we have reported low circulating levels of branched‐chain amino acid in active ACRO [80]. This finding could contribute to the myopathy observed in patients with ACRO, but further basic and clinical research on this issue is needed. In this regard, Int. J. Mol. Sci. 2021, 22, 415 10 of 18 Recently, we have reported low circulating levels of branched-chain amino acid in active ACRO [80]. This finding could contribute to the myopathy observed in patients with ACRO, but further basic and clinical research on this issue is needed. In this regard, to the best of our knowledge, there are no studies addressed to investigate the potential role on muscle performance of diet enriched with AA in ACRO. 6. Impact of GH/IGF-1 Axis Impairment on Muscle Metabolism and Function: Lessons from Basic Research The GH and IGF-1-mediated regulation of skeletal muscle structure and performance have recently been reviewed [54,81,82]. We will focus on the impact on the muscle of diseases with low or excess GH/IGF-1. 6.1. Primary Cell Cultures In vitro studies using immortalised the mouse myoblast cell line C2C12 has provided preliminary evidence regarding the action of IGF-I in muscle stimulating muscle protein synthesis, and also in suppressing proteolysis [83]. IGF-1 is also related to myoblast proliferation [84] and differentiation [54]. In addition, IGF-1 modulates the expression of L-type amino acid transporters in the muscles of spontaneous dwarf rats [85]. Mahendra et al. (2010) [86], in an elegant work using cell lines of mice lacking either the GH receptor or the IGF-1 receptor in skeletal muscle, found that GH mediates skele- tal muscle development by enhancing myoblast fusion in an IGF-1-dependent manner. They showed that GH treatment quickly increases IGF-1 mRNA and that this autocrine production of IGF-I leads to a significant increase in primary myoblast proliferation. By con- trast, disruption of the GH receptor in skeletal muscle produces marked alterations in muscle nutrient uptake and insulin sensitivity in an IGF-1-independent manner. Altogether, these findings indicate that the myoblast anabolic process is a complex action where both hormones are complementary. Nevertheless, metabolic dysfunctions seem to be more related to GH impairment. 6.2. Transgenic Mice Several genetically modified animal models (giants and dwarfs) have been gener- ated and characterised in the last 30 years [87–89] and have been used to investigate the phenotype, consequences and mechanisms underlying the altered GH/IGF-1 axis [90] This review will focus on the most relevant ones: transgenic mice overexpressing GH and GH knockout mice. For comprehensive reviews, please see references [87,91–93]. High GH levels in transgenic mice have elevated GH and IGF-1 levels, increased body weight, and lean mass. The extreme elevation in circulating GH also results in hyperinsulinemia despite euglycemia, probably due to reduced insulin receptors or GLUT4 channels in skeletal muscle. There are some differences among the various GH transgenes species in mice (e.g., ovine GH, bovine GH or human GH). Human GH can bind to both GH and prolactin (PRL) receptors, whereas rat, bovine and ovine GH bind exclusively to GHR. Thus, overexpression of human GH in mice results in a physiological state in which both GH and PRL receptors are simultaneously activated in contrast with rat, bovine, or ovine where only GHR is activated [92]. Together with the different ages of the mice used in the experiments, these differences could explain the heterogeneity of the published results regarding body composition. Besides, the following aspects should be taken into account when using transgenic mice: (1) In ACRO, GH secretion is from a pituitary adenoma whereas, in GH transgenic mice, GH excess is due to transgene insertion resulting in ectopic GH secretion. (2) The level of circulating GH is often markedly greater in transgenic mice than is observed in ACRO. (3) Transgenic mice exposure to excessive GH begun immediately after birth mimics gigantism more than ACRO (4) in human transgenic mice, GH and PRL receptors are simultaneously activated, unlike in ACRO. In complete contrast to high GH level transgenic mice, there are the dwarfism models: The GH knockout mice (GHKO or GH−/−), completely lack GH due to a targeted deletion of the GH gene. These mice represent a model of human isolated GH deficiency. The GH Int. J. Mol. Sci. 2021, 22, 415 11 of 18 receptor gene disrupted mice (GHR−/−) are mice completely resistant to GH action; they also have a pronounced decrease in body size with extremely low circulating IGF-1 de- spite elevated GH levels and constitute the model for LS. Other types of dwarfism models are transgenic IGF-1 knockout mice. Although the animals are born alive, mortality rates range from 32% to 95% due to respiratory failure caused by impaired diaphragm develop- ment, severe muscle dystrophy and intercostal muscles. These mice also develop metabolic abnormalities such as mild hyperglycaemia (250 mg/dl) and decreased pancreatic beta cells [63,94]. Finally, another model of IGF-1 deficiency is a consequence of a deletion of the gene encoding the IGF-1 in the liver (only in the liver, not in other tissues), resulting in a 75% reduction of circulating plasma IGF-1 levels [95]. These animals usually grow and are fertile. It has been suggested that high levels of growth hormone and increased paracrine or tissue IGF-1 levels compensate for the lower plasma levels of IGF-1. Overall, these findings provide evidence that both GH and IGF-1, including locally muscular secreted IGF-1, have active implications for growth and muscle development. 6.3. Experimental Research Focused on the GH/IGF-1 System Effects on Muscle The effects of GH deficiency in muscle have been controversial. Ayling et al. (1989) [96] reported a 50% reduction in type I fibres after rat hypophysectomy, that recovered after GH therapy. Similar results were obtained by Loughna and Bates five years later (1994) [97]. By contrast, Yamaguchi et al. (1996) [98] also observed a significant increase in type I fibres after rat hypophysectomy. Some studies have also reported no change in the composition of type I or type II fibres after GH replacement in the same experimental model [99]. These divergent results could be explained by the different exposure to GHD, GH therapy duration, and the associated deficit of other hormones such as thyroxine, testosterone and glucocorticoids. Nielsen et al. (2014) [100] in an elegant work, measured the ultra-structure and collagen in the Achilles tendon, employing three groups of mice: (1) Giant transgenic mice that expressed bovine GH (bGH): the ACRO model; (2) Dwarf mice disrupted GH receptor GHR−/− (the LS model) and (3) A wild-type control group. They found that the mean collagen fibril diameter was significantly decreased in the ACRO and LS models. The ultra-structural pattern was more severely affected in the GHR−/− mouse model. Similarly, a recent study of Cinaforlini et al. (2020) [101] investigated muscle repair and found that GH administration accelerated the muscle healing process. Regarding the direct effect of IGF-1 on the muscle, Schoenle et al. in 1982 [102] reported that IGF-1 stimulated growth in hypophysectomised rats, thus providing evidence of independent IGF-1 action from GH. DeVol et al. in 1990 described for the first time the local skeletal muscle production of IGF-1 [58]. Using a rat model of compensatory hypertrophy of the soleus, the authors showed that muscle hypertrophy and local IGF-1 production occurred independently of GH. However, compensatory hypertrophy was not blunted in hypophysectomised rats. All this evidence reinforces the concept that although the actions of GH and IGF1 in the muscle, are independent, they are complementary. 7. The Muscle in GH/IGF1 Axis Deficiency Isolated GH deficiency (IGHD) either congenital or acquired, is the commonest pi- tuitary hormone deficiency [103]. First description and treatment date from 1963 [104]. During childhood and puberty, the classical phenotype of GHD is short stature with height ≤ −2 SDS, frontal bossing, mid-facial hypoplasia (“doll-like” facies) and truncal adipos- ity [105]. Adult-onset patients with GHD have increased total and visceral fat, low bone mass, reduced muscle strength and impaired anaerobic physical capacity, an unfavourable cardiovascular profile, and low quality of life [106,107]. There is conflicting data regarding body composition and muscle structure and perfor- mance after GH treatment. In a recent study, Andrade-Guimarães et al. (2019) [108] found Int. J. Mol. Sci. 2021, 22, 415 12 of 18 that individuals with congenital untreated IGHD had better muscle strength parameters adjusted for weight and fat-free mass than controls, and also exhibited greater peripheral resistance to fatigue. In adults with GHD, Díez et al. (2018) [109] and Jørgensen et al. (2018) [107] among others, argued in favour of the beneficial effects of GH administration on body composition, muscle exercise capacity, bone structure and serum lipids. By contrast, He and Barkan (2020) [110] critically reviewed the evidence of treatment benefits in adult-onset GHD. They found most of the data inconsistent, thus recommending that GH treatment should be a personalised decision. Regarding GH resistance (LS) syndrome, the main clinical characteristics are dwarfism, specific facial features such as a protruding forehead in the presence of a subnormal head circumference, sparse hair, skeletal and muscular underdevelopment, obesity and underdeveloped genitalia [111]. Long-term observations have shown that these individuals are protected from cancer [112,113]. In relation to the muscle, they have a reduced lean body mass and reduced muscle force and endurance [114]. Curiously, growth velocity obtained with IGF-I administration is smaller than that observed with hGH in children with congenital isolated GH deficiency [115]. Muscle benefit with IGF-1 therapy has not been fully established. Long-term treatment for adult patients living with LS aimed at strengthening the muscular and skeletal systems is not currently approved. 8. Muscle Impairment in Human Acromegaly Muscular weakness and pain represent one of the significant disabling co-morbidities in ACRO [5,116] and, as above mentioned, despite long-term remission of the disease, this co-morbidity may persist and deeply compromise QoL. Although musculoskeletal pain is reported in up to 90%, it is not usually recorded in the clinical history [116]. It should be noted that as a result of treatment improvement, life expectancy in people living with ACRO is currently comparable to that of the general population [117] and, therefore, the rate of musculoskeletal impairment is not expected to be reduced. Nevertheless, this is one of the least studied co-morbidities [118], and there are few studies focused on the evolution of myopathy after ACRO treatment. Mastaglia et al. in 1970 [119] reported for the first time on muscle impairment in ACRO. Mild proximal muscle weakness was present in six out of 11 cases. Histological changes in hypertrophy of both type-I and type-II muscle fibres were current in five out of nine biopsy specimens taken from a proximal limb muscle. However, electron microscopy showed a patchy myopathy process, thus accounting for these patients’ weakness and myalgia. By contrast, Nagulesparen et al. (1976) [120] studied 18 patients with acromegaly of varying degrees of severity; half of the specimens showed hypertrophy of type 1 fibres, and atrophy in type 2 fibres, although a direct correlation between muscle appearances and growth hormone levels was not observed. These findings suggest, firstly, a dissociation between muscle macro/microstructure and the IGF-1/GH level, and secondly an alteration in the damage repair mechanism in acromegaly. Thus, other factors independently of hormone levels could play a key role in ACRO myopathy, and treatments strengthening the muscle damage repair mechanism could improve this co-morbidity. Concerning energy consumption, Szendroedi et al. (2008) [121], found that patients with ACRO exhibited reduced muscular ATP synthesis and oxidative capacity that may persist despite the normalisation of GH secretion. Regarding strength, Füchtbauer et al. (2017) [5] studied ACRO patients at diagnosis (n = 48), one year after surgery (n = 29) and after long-term follow-up (median 11 years) (n = 24), compared to healthy subjects. They found reduced grip and strength in active ACRO and increased proximal muscle fatigue even after GH/IGF-1 normalisation. Although the most apparent muscular structural change in active ACRO seemed to be hypertrophy [122,123], more recent studies, have not confirmed this finding [124]. Recently Gokce et al. (2020) [125] using ultrasound found that the thicknesses of many Int. J. Mol. Sci. 2021, 22, 415 13 of 18 components of the quadriceps muscle were lower in ACRO patients than control subjects matched by age, sex and the body mass index. We have very little evidence on interventional programs to improve this devastating co-morbidity. However, Lima et al. (2019) [6] evaluated the effects of a functional home rehabilitation program in seventeen adults with ACRO that resulted in improvements in muscle function, functional capacity, general fatigue, body balance, and QoL. Accordingly, other therapeutic strategies apart from GH/IGF-1 normalisation, with a direct impact on muscle structure/performance should be followed to improve our patients QoL. 9. Concluding Remarks and Future Perspectives In ACRO, the sustained increase of GH and IGF-1 critically affects the skeletal, muscu- lar system with severe repercussions on life quality. At present, our knowledge regarding the underlying mechanisms and outcome of different treatments is scarce. In addition, there are no clinical guidelines or any structured recommendations for dealing with this debilitating co-morbidity. Therefore, there is a pressing need to promote interaction between basic and clinical research, improving our knowledge and permitting us to design therapeutic strategies. Nevertheless, we can remark on some important points: (1) Up to 90% of ACRO patients suffer from musculoskeletal pain. (2) This co-morbidity may persist despite biochemical control of the disease and deeply compromise QoL. (3) Other factors apart from GH/IGF-1 levels could have a significant role in ACRO myopathy’s underlying mechanism. (4) New biomarkers linking muscle mass and metabolism to diagnose better and phenotype myopathy and design the best therapeutic strategy are needed. Cell lines and transgenic mice give important insights into the many actions of GH and IGF-1. The degree of the contribution of GH or IGF-1 to myopathy in acromegaly remains to be further investigated. In the clinical setting, we need (1) tools that efficiently and reliably permit us to evaluate the muscular status of patients with ACRO, (2) collaborative, multicentre studies with larger samples to provide more accurate data, and (3) further studies that investigate treatments that directly influence muscle performance, even in patients in remission. Finally, it should be emphasised that the muscle should be seen as a key role organ, with mechanical and metabolic functions. Disturbances in metabolic processes (for ex- ample, hyperglycaemia, amino acid deficiency) can ultimately impact muscle structure and, vice versa, changes in fibre type can promote metabolic changes. In this regard, studies aimed at assessing the molecular link between structural changes and metabolic function are needed. Author Contributions: Both authors equally contributed to the conception of the review. B.B. drafted the work and R.S. revised it critically for important intellectual content. B.B. and R.S. gave final approval of the version of the manuscript; and agree to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. 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