ORIGINAL RESEARCH published: 15 October 2021 doi: 10.3389/fphys.2021.744632 The Second Wind in McArdle Patients: Fitness Matters Eduardo Salazar-Martínez 1† , Alfredo Santalla 2,3† , Pedro L. Valenzuela 4 , Gisela Nogales-Gadea 5 , Tomàs Pinós 6,7 , María Morán 6,8 , Alejandro Santos-Lozano 9,10 , Carmen Fiuza-Luces 10* ‡ and Alejandro Lucia 4,10‡ 1 Centro de Estudios Universitarios Cardenal Spínola-CEU, Seville, Spain, 2 Department of Sports and Computing, Pablo de Olavide University, Seville, Spain, 3 EVOPRED Research Group, Universidad Europea de Canarias, Tenerife, Spain, 4 Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain, 5 Neuromuscular and Neuropediatric Research Group, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain, 6 Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain, 7 Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain, 8 Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), Madrid, Spain, 9 i+HeALTH, European University Miguel de Cervantes, Valladolid, Spain, 10 Physical Activity and Health Research Group, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), Madrid, Spain Background: The “second wind” (SW) phenomenon—commonly referring to both an Edited by: initial period of marked intolerance to dynamic exercise (e.g., brisk walking) that is not Francesca Lanfranconi, University of Milano-Bicocca, Italy followed by perceived improvement and disappearance of previous tachycardia (i.e., the Reviewed by: actual “SW”) until 6–10 min has elapsed—is an almost unique feature of McArdle disease Cristiano Eirale, that limits adherence to an active lifestyle. In this regard, an increase in the workload Paris Saint-Germain F.C., France eliciting the SW could potentially translate into an improved patients’ exercise tolerance Giuseppe Lanza, University of Catania, Italy in daily life. We aimed to determine whether aerobic fitness and physical activity (PA) *Correspondence: levels are correlated with the minimum workload eliciting the SW in McArdle patients— Carmen Fiuza-Luces as well as with the corresponding heart rate value. We also compared the SW variables cfiuza.imas12@h12o.es † These and aerobic fitness indicators in inactive vs. active patients. authors share first authorship ‡ These authors share senior Methods: Fifty-four McArdle patients (24 women, mean ± SD age 33 ± 12 years) authorship performed 12-min constant-load and maximum ramp-like cycle-ergometer tests for Specialty section: SW detection and aerobic fitness [peak oxygen uptake (VO2peak ) and workload and This article was submitted to ventilatory threshold] determination, respectively. They were categorized as physically Exercise Physiology, active/inactive during the prior 6 months (active = reporting ≥150 min/week or a section of the journal Frontiers in Physiology ≥75 min/week in moderate or vigorous-intensity aerobic PA, respectively) and were also Received: 20 July 2021 asked on their self-report of the SW. Accepted: 27 September 2021 Published: 15 October 2021 Results: Both peak and submaximal indicators of aerobic fitness obtained in the ramp Citation: tests were significantly correlated with the workload of the SW test, with a particularly Salazar-Martínez E, Santalla A, strong correlation for the VO2peak and peak workload attained by the patients (both Valenzuela PL, Nogales-Gadea G, Pearson’s coefficients > 0.70). Twenty (seven women) and 24 patients (18 women) were Pinós T, Morán M, Santos-Lozano A, Fiuza-Luces C and Lucia A (2021) categorized as physically active and inactive, respectively. Not only the aerobic fitness The Second Wind in McArdle level [∼18–19% higher values of VO2peak (ml·kg−1 ·min−1 )] but also the workload of Patients: Fitness Matters. Front. Physiol. 12:744632. the SW tests was significantly higher in active than in inactive patients. All the inactive doi: 10.3389/fphys.2021.744632 patients reported that they experienced the SW during walking/brisk walking in daily Frontiers in Physiology | www.frontiersin.org 1 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles life, whereas active patients only reported experiencing this phenomenon during more strenuous activities (very brisk walking/jogging and bicycling). Conclusion: A higher aerobic fitness and an active lifestyle are associated with a higher workload eliciting the so-called SW phenomenon in patients with McArdle disease, which has a positive impact on their exercise tolerance during daily living. Keywords: glycogenosis type 5, myophosphorylase deficiency, cardiorespiratory fitness, ventilatory threshold, physical activity second wind in McArdles 2 INTRODUCTION Spanish patients report experiencing the SW during daily life (Santalla et al., 2017). McArdle disease [glycogen storage disease (GSD) type 5] McArdle patients typically show low levels of physical is an autosomal recessive disorder caused by deficiency of activity (PA; Santalla et al., 2017) and poor aerobic fitness, the skeletal-muscle isoform of glycogen phosphorylase — well below age- and sex-matched normative values (Munguia- “myophosphorylase” — which catalyzes the first step of glycogen Izquierdo and Lucia, 2015) [e.g., mean ± SD values of peak metabolism (Santalla et al., 2014). Patients are therefore unable oxygen uptake (VO2peak ) of 19.9 ± 6.6 in Spanish patients to obtain energy from their muscle glycogen stores. Yet, because (Santalla et al., 2017) or median values of 18.5 ml·kg−1 ·min−1 the metabolic blockade occurs upstream of the uptake of this in European patients (Scalco et al., 2020)]. In turn, VO2peak substrate into patients’ muscle fibers, the latter can utilize is significantly higher in physically active patients than in circulating glucose. This disorder is arguably the paradigm of their inactive peers (Santalla et al., 2017) and previous studies “exercise intolerance” (Di Mauro, 2007; Santalla et al., 2014), have shown the benefits of regular, low-moderate intensity characterized by the occurrence of early exertional fatigue, aerobic exercise training (bicycling, brisk walking) to increase together with muscle weakness, myalgia, and muscle contractures the VO2peak of McArdle patients (Haller et al., 2006; Mate- associated with exertion, often accompanied by “crises” of Munoz et al., 2007; Porcelli et al., 2016). These results are rhabdomyolysis (Lucia et al., 2008; Santalla et al., 2014, 2017; in line with the finding that tailored low-moderate aerobic Scalco et al., 2020). exercise might be not only safe (Stefanetti et al., 2020) but Except for a recently described case in phosphoglucomutase also useful to improve patients’ physical function in the type 1 deficiency (GSD type 14; Preisler et al., 2017), a unique context of several neurological or neuromuscular disorders, feature shown by patients with McArdle disease is the so-called even including degenerative conditions [e.g., amyotrophic lateral “second wind” (SW). Thus, these patients typically experience an sclerosis (Meng et al., 2020) or Becker’s muscular dystrophy initial period of marked intolerance to dynamic exercise (e.g., (Lanza et al., 2020b)]. Other modalities, such as constant, brisk walking) that is not followed by an improvement (perceived individually tailored, high-intensity motor training might be by the patients as an “SW,” with subsequent disappearance of effective in patients with degenerative ataxia, including those with previous tachycardia) after 6–10 min has elapsed (Di Mauro, severe disease (Lanza et al., 2020a). 2007). Of note, although the SW per se (and properly speaking) However, the influence of aerobic fitness or PA levels on the refers to the aforementioned second phase of improved exercise presentation of the SW remains unknown. This is an important tolerance, in practical terms (and also herein) the concept of consideration because an increase in the workload eliciting “SW” is commonly used to refer to both the initial phase of the SW would potentially translate into an improvement in exercise intolerance and the subsequent SW phase. The SW is patients’ exercise tolerance during daily life. The purpose of easily measurable in the laboratory by simply monitoring the this study was therefore to determine whether aerobic fitness or heart rate (HR) response during a constant-load cycle-ergometer PA levels are positively correlated with the minimum workload test, which can be used as a diagnostic tool of the disease (Di that elicits the SW phenomenon in McArdle patients (as well Mauro, 2007). The physiological mechanisms explaining the SW as with the corresponding HR value obtained) during a cycle- have been previously studied. The first few minutes of exercise act ergometer constant-load test. We also compared SW variables as a warm-up (inducing muscle vasodilation), after which more and aerobic fitness indicators in active vs. inactive patients. Our circulating free fatty acids and especially glucose are available main hypothesis was that aerobic fitness is overall positively to working muscle fibers; therefore, the upstream blockade associated with the workload eliciting the SW, with the latter in glycogenolysis is partially bypassed, leading to considerable being higher in active than in inactive patients. attenuation of early fatigue (Haller and Vissing, 2002). The first phase of the overall SW phenomenon is commonly reported by patients as the need to take a rest when they start a MATERIALS AND METHODS usual exercise task of daily living such as walking (Santalla et al., 2017), and therefore interferes with their normal daily Participants activities and potentially detracts them from leading a more The study protocol was approved by the local ethics active lifestyle. For instance, the vast majority of all diagnosed committee and all the participants gave their written informed Frontiers in Physiology | www.frontiersin.org 2 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles consent. The study was performed from September 2012 to SW test and highest HR value recorded during this test). We December 2016 in the exercise physiology laboratory of the also compared SW variables in inactive vs. active patients with Universidad Europea de Madrid (UEM). Inclusion criteria the non-parametric Mann Whitney U test. The magnitude of were: (i) diagnosis of McArdle disease, as ascertained by the the differences was assessed through the computation of effect identification of a documented pathogenic mutation in both sizes (Hedge’s g). The level of significance was set at 0.05 and alleles — whether in homozygosity or heterozygosity — data analysis was performed using the SPSS statistical software of the gene (PYGM) encoding myophosphorylase; (ii) package (PASW Statistic 25). being free of any major cardiorespiratory disease or severe condition contraindicating exercise; (iii) reporting the SW; and (iv) having previous exercise testing experience RESULTS in our laboratory. Fifty-four patients with McArdle disease that met all the inclusion Exercise Tests criteria (30 men and 24 women, mean ± SD age 33 ± 12 years All participants visited the UEM laboratory in the morning [range 11–59], body mass index [BMI] 24.8 ± 4.8 kg·m−2 ) agreed after an overnight fast. Before testing, they were categorized as to participate in this study. The PYGM genotype data are shown physically active or inactive during the prior 6 months [i.e., in Supplementary File 1. active = reporting ≥ 150 min/week in moderate-intensity aerobic The mean physiological responses to the SW and ramp- PA or ≥75 min/week in vigorous-intensity aerobic PA (Bull like tests are shown in Table 1. The HR response in the et al., 2020)]. Patients were also asked on their self-report of SW tests is graphically shown in Figure 1. Both peak and the SW phenomenon (i.e., what type of PA or exercise elicits submaximal indicators of aerobic fitness obtained in the ramp this phenomenon). tests were significantly correlated with the workload of the SW All the tests were performed using the same cycle-ergometer test (Table 2), with a particularly strong correlation found for the (Ergoselect 220 KL; Ergoline GmbH, Bitz, Germany) and VO2 peak (Figure 2A), and peak workload (Figure 2B) attained metabolic cart (Vmax 29C; Sensormedics Corp., Yorba Linda, by the patients (both Pearson’s coefficients >0.70). CA, United States), with the latter used to record ECG- Twenty (7 women) and 24 patients (18 women) were determined HR values and expired gas data. First, and based categorized as physically active and inactive, respectively. Not on previous data from each participant, the patients pedaled only the aerobic fitness level — notably, ∼18–19% higher values for ∼3–4 min, and we adjusted the workload (watts) with of VO2peak in ml·kg−1 ·min−1 — but also the workload of the SW gentle increases starting from 0 watts (i.e., 5 watts/30 s) tests was significantly higher in active than in inactive patients such as to identify the minimum workload eliciting an HR (Table 3). These results remained overall unchanged in separate value of ≥65% of the age-predicted maximum HR (220 min analyses for female (Supplementary File 2) or male patients age, in years). Once this “target” workload was identified (Supplementary File 3), respectively. On the other hand, all the (usually in ≤3 min), the participants immediately stopped inactive patients reported that they experienced the SW during pedaling and rested for 1 h. Thereafter, they performed a walking or brisk walking in daily life whereas active patients only “diagnostic” 12-min constant-load test for SW identification reported experiencing this phenomenon during more strenuous at the identified target workload (Vissing and Haller, 2003). activities, such as very brisk walking/jogging or bicycling. Participants then rested for ∼45 min before they performed a maximum test until exhaustion as detailed elsewhere (Mate- TABLE 1 | Physiological responses to the second wind and ramp tests in all Munoz et al., 2007). The maximum test was preceded by a participants (n = 54). 5-min free-wheel pedaling warm-up, after which the workload was increased following a ramp protocol (10 watts/min) until Variable 12-min constant Ramp test until exhaustion workload test for volitional exhaustion (Mate-Munoz et al., 2007). The VO2peak second wind Ventilatory Peak values was determined as the highest VO2 value (20-s average) detection* threshold recorded during the tests, whereas the workload eliciting the VT was visually identified by two independent investigators VO2 (ml·min−1 ) 864 ± 256 793 ± 229 1,316 ± 356 (or by a third one in case of disagreement) as the workload VO2 (ml·kg·min−1 ) 12.5 ± 3.9 11.2 ± 3.0 18.8 ± 5.0 eliciting an increase in the 20-s average value of the ventilatory Power output (watts) 31 ± 11 37 ± 15 82 ± 23 equivalent for oxygen (VE/VO2 ), with no concomitant increase HR (bpm) 147 ± 21 116 ± 15 161 ± 21 in the ventilatory equivalent for carbon dioxide (VE/VCO2 ; VE (l·min−1 ) 25.7 ± 10.9 20.2 ± 5.9 41.8 ± 15.5 Mate-Munoz et al., 2007). RER 0.84 ± 0.07 0.82 ± 0.09 0.91 ± 0.12 % of age-predicted 79 ± 11 73 ± 9 86 ± 10 Statistics Analysis HRmax Data are expressed as mean ± standard deviation. The Abbreviations: HR, heart rate; HRmax, maximum heart rate (age distribution of data was studied with the Kolmogorov–Smirnov predicted = 220 min age in years); RER, respiratory exchange ratio; VE , pulmonary ventilation; and VO2 , oxygen uptake. test. Pearson correlation analyses were used to assess the Symbol: *Average values for all variables correspond to the highest 10-s value of relationship between aerobic fitness indicators and variables HR obtained during the constant-load test for second wind detection (which on related to the SW phenomenon (i.e., workload of the diagnostic average was reached at 6 min 35 ± 94 s). Frontiers in Physiology | www.frontiersin.org 3 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles FIGURE 1 | Graphical representation of the heart rate response during second wind tests by sex (A) or physical activity levels (B). Data are mean ± SEM (for each 1-min period), with no statistical comparisons done. DISCUSSION higher VO2peak values reported in physically active patients (20.7 ± 6.0 ml·kg−1 ·min−1 ) than in their inactive referents The main finding of this study was the association between (16.8 ± 5.3 ml·kg−1 ·min−1 ; Santalla et al., 2017). In this context, aerobic fitness indicators (VO2peak and VT) and the workload our data also provide additional rationale supporting the need to eliciting the SW in patients with McArdle disease, as well as the increase the aerobic fitness as well as the levels of aerobic PA in fact that the latter corresponded to considerably higher power patients with McArdle disease because a previously unreported output levels (by 35%) in active than in inactive patients. This benefit associated with a higher aerobic fitness level and an had a translation into patients’ daily life, as in fact corroborated active lifestyle is an increase in the workload eliciting the SW. by their own self-reports — that is, active patients did not This is an important consideration when keeping in mind that experience the SW during non-strenuous activities in daily living. aerobic (or “cardiorespiratory”) fitness (commonly assessed as Therefore, the present findings would support the importance of VO2peak ) is a strong prognostic factor of morbidity and mortality increasing PA levels and improving aerobic fitness in this patient from all causes and, particularly, from cardiometabolic disease population. On the other hand, the main limitation of our study (Lavie et al., 2019). Recent data from the European registry is the cross-sectional design we used, whereas a major strength of patients with McArdle disease indicate a rather unhealthy is the large sample of patients we assessed and the novelty of the cardiometabolic profile for these patients, with two-thirds of question addressed. them showing high BMI values and ∼12% having cardiovascular Recent research from our group has shown that McArdle disease (8% with coronary artery disease) despite the relatively patients who are physically active are 14-fold more likely to young age of the cohort (median age 46 years), likely reflecting report an improvement after a 4-year period in the clinical a sedentary lifestyle related to the poor exercise tolerance and course of the disease compared with their inactive peers, with muscle pain on exertion (Scalco et al., 2020). Frontiers in Physiology | www.frontiersin.org 4 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles TABLE 2 | Correlation between aerobic fitness (obtained in ramp-like tests) and potential ([ATP]/[ADP][phosphate]) leads to the accumulation second wind (SW) variables. of phosphate, and probably also ADP, in patients’ muscles, Aerobic fitness Power output (watts) Highest HR† (bpm) value thereby inhibiting myofibrillar ATPase, calcium pump, and indicators in SW tests attained in SW tests sodium-potassium pump reactions and leading to premature muscle fatigue and contractures (Lewis and Haller, 1986). Yet, VO2 peak (ml·min−1 ) 0.706** 0.173 recent findings from our group in the mouse model of the disease VO2peak (ml·kg·min−1 ) 0.449** 0.306* would indicate that myophosphorylase deficiency causes no Peak power output (watts) 0.804** 0.081 major alterations in muscle oxidative phosphorylation capacity VO2 @VT (ml min−1 ) 0.613** 0.137 or autophagy/ubiquitination pathways, thereby suggesting that VO2 @VT (ml·kg−1 min−1 ) 0.356** 0.279* the patients’ muscle tissue is likely to adapt overall favorably Power output @VT (watts) 0.613** 0.042 to regular exercise (Fiuza-Luces et al., 2016). In fact, Haller Data are Pearson’s correlation coefficients. Abbreviations: HR, heart rate; VO2peak , et al. (2006) have shown improvements after training in patients’ peak oxygen uptake; and VT, ventilatory threshold. muscle oxidative capacity (i.e., increase in the activity of Symbols: *p < 0.05; **p < 0.01; † 10-s averages. the mitochondrial enzymes citrate synthase and hydroxyacyl coenzyme A dehydrogenase). One of the hallmarks of McArdle disease (which was also Besides the prognostic value of the VT in diseased people in corroborated here) is the very poor aerobic fitness of affected general (Meyer et al., 2005), the occurrence of the VT (sometimes patients (Munguia-Izquierdo and Lucia, 2015; Santalla et al., known as “anaerobic threshold”) in McAdle patients is an 2017; Scalco et al., 2020). Traditionally, a major reason for interesting finding. Indeed, despite not showing lactic acidosis this phenomenon has been attributed to an impairment of during exercise due to the blockade of glycogenolysis — blood the patient’s muscle oxidative capacity because the ability to lactate values only average ∼2 mmol·l−1 at the end of a ramp-like produce pyruvate — a molecule that plays an anaplerotic role test until exhaustion like the one used here (Mate-Munoz et al., in the Krebs cycle — is severely reduced (Lucia et al., 2008). 2007) — these patients show a threshold-like ventilatory response The impairment in the rate of oxidative phosphorylation is similar to that of healthy people, as shown in a classic study reflected on phosphorus magnetic resonance spectroscopy (31P- (Whipp, 1983) and corroborated by us both in previous research MRS) by remarkably greater phosphocreatine consumption and (Mate-Munoz et al., 2007) and in the present study. Thus, the lower ATP concentrations compared to healthy controls after hyperventilation that accompanies high-intensity exercise may be submaximal isometric calf contractions (Zange et al., 2003). The the result of some mechanism other than acidosis or lung CO2 resultant marked decrease in skeletal muscle phosphorylation flux (Hagberg et al., 1990), with these patients maybe exhibiting FIGURE 2 | Correlation between peak oxygen uptake (VO2peak , A) and peak workload (B) attained by the patients during the ramp-like tests and the minimum workload eliciting the second wind phenomenon. Frontiers in Physiology | www.frontiersin.org 5 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles Data are presented as Mean ± SD and Hedge’s g effect size (ES). Abbreviations: HRmax, maximum heart rate (age predicted = 220 min age in years); RER, respiratory exchange ratio; VE, pulmonary ventilation; VO2 , Symbols: *average values for all variables correspond to the highest 10-s value of HR obtained during the constant-load test for second wind detection (which on average was reached at 6 min 35 s ± 94 s); **detectable a mechanism for the ventilatory drive which compensates for ES (Hedge’s the lack of blood acidosis. One of such mechanisms might 0.78 0.79 0.59 0.32 0.00 0.38 g) – be adenosine released from muscles (Rubio et al., 2008), with extracellular adenosine able to stimulate ventilation not only between through activation of carotid chemoreceptors but also through p-value groups <0.001 an effect mediated by sensory lung receptors innervated by 0.008 0.044 0.546 0.932 0.168 unmyelinated vagal C fibers (Burki et al., 2005). Peak values In summary, a higher aerobic fitness and an active lifestyle are associated with a higher workload eliciting the so-called 40.1 ± 12.3 0.91 ± 0.13 17.4 ± 4.6 Inactive 75 ± 19 156 ± 20 SW phenomenon in patients with McArdle disease, which in 85 ± 9 – turn has a beneficial impact on their daily living — that is, improved exercise tolerance. Interventional research is needed Ramp test until exhaustion 45.4 ± 20.8 to determine which is the best type of exercise/PA intervention 21.1 ± 4.7 0.91 ± 0.1 93 ± 27 168 ± 20 89 ± 12 Active to elicit the largest possible improvements in the minimum – workload eliciting the SW. ES (Hedge’s TABLE 3 | Physiological responses to the second wind and ramp tests in physically active (n = 20; 7 women) vs. inactive participants (n = 34; 18 women). DATA AVAILABILITY STATEMENT 0.34 1.27 1.19 0.98 0.41 0.01 0.30 g) The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be Ventilatory threshold** between directed to the corresponding author/s. p-value groups <0.001 0.226 0.008 0.001 0.245 0.808 0.344 ETHICS STATEMENT 60.7 ± 11.1 31.0 ± 10.2 0.81 ± 0.10 10.2 ± 2.1 19.5 ± 4.1 Inactive 111 ± 15 72 ± 9 The studies involving human participants were reviewed and approved by Hospital 12 de Octubre. The patients/participants provided their written informed consent to 65.1 ± 14.8 47.8 ± 18.6 0.81 ± 0.08 participate in this study. 13.5 ± 3.2 21.7 ± 6.8 125 ± 12 75 ± 11 Active AUTHOR CONTRIBUTIONS 12-min constant load test for second wind detection* ES-M, AS, CF-L, and AL: data collection (exercise evaluations). AS and AL: conception. GN-G and TP: data collection (molecular ES (Hedge’s genetics for diagnosis). PV, AS-L, and MM: data analysis. MM: 0.35 0.86 0.91 0.38 0.13 0.35 g) 1.1 supplying of important material. ES-M, AS, and AL: drafting of the manuscript. All authors provided important feedback for the manuscript edition. between p-value groups 0.425 0.003 0.002 0.076 0.145 0.490 0.217 FUNDING 0.85 ± 0.05 0.84 ± 0.08 11.5 ± 3.5 24.8 ± 7.9 Inactive 66 ± 12 28 ± 10 78 ± 11 Research by AL, CF-L, GN-G, MM, and TP was funded by 144 ± 2 the Instituto de Salud Carlos III (ISCIII) and Fondos Feder (grants PI18/00139, PI20/00645, PI18/00713, PI17/00093, and oxygen uptake; VO2peak , peak oxygen uptake. PI19/01313). CF-L and GN-G were supported by Miguel Servet 14.6 ± 3.6 28.1 ± 9.3 71 ± 17 38 ± 12 155 ± 16 82 ± 11 Active contracts (CP18/00034 and CPII19/00021, respectively) from ISCIII. The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; Significant p-values are in bold. or in the decision to submit the manuscript for publication. % age-predicted HRmax Power output (watts) SUPPLEMENTARY MATERIAL (ml·kg−1 ·min−1 ) in all patients. % VO2peak The Supplementary Material for this article can be found online Variable (l·min−1 ) at: https://www.frontiersin.org/articles/10.3389/fphys.2021. (bpm) RER VO2 HR VE 744632/full#supplementary-material Frontiers in Physiology | www.frontiersin.org 6 October 2021 | Volume 12 | Article 744632 Salazar-Martínez et al. Second Wind in McArdles REFERENCES Porcelli, S., Marzorati, M., Morandi, L., and Grassi, B. (2016). Home-based aerobic exercise training improves skeletal muscle oxidative metabolism in patients Bull, F. C., Al-Ansari, S. S., Biddle, S., Borodulin, K., Buman, M. P., Cardon, G., with metabolic myopathies. J. Appl. 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Favorable responses to acute and chronic exercise Publisher’s Note: All claims expressed in this article are solely those of the authors in McArdle patients. Clin. J. Sport Med. 17, 297–303. doi: 10.1097/jsm. and do not necessarily represent those of their affiliated organizations, or those of 0b013e3180f6168c the publisher, the editors and the reviewers. Any product that may be evaluated in Meng, L., Li, X., Li, C., Tsang, R. C. C., Chen, Y., Ge, Y., et al. (2020). Effects of this article, or claim that may be made by its manufacturer, is not guaranteed or Exercise in patients with amyotrophic lateral sclerosis: a systematic review and endorsed by the publisher. meta-analysis. Am. J. Phys. Med. Rehab. 99, 801–810. Meyer, T., Lucía, A., Earnest, C. P., and Kindermann, W. (2005). A conceptual Copyright © 2021 Salazar-Martínez, Santalla, Valenzuela, Nogales-Gadea, Pinós, framework for performance diagnosis and training prescription from Morán, Santos-Lozano, Fiuza-Luces and Lucia. This is an open-access article submaximal gas exchange parameters–theory and application. Int. J. Sports distributed under the terms of the Creative Commons Attribution License (CC BY). Med. 26, S38–S48. The use, distribution or reproduction in other forums is permitted, provided the Munguia-Izquierdo, D. S., and Lucia, A. (2015). Cardiorespiratory fitness, physical original author(s) and the copyright owner(s) are credited and that the original activity, and quality of life in mcardle patients. Med. Sci. Sports Exe. 47, 799–808. publication in this journal is cited, in accordance with accepted academic practice. No doi: 10.1249/mss.0000000000000458 use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Physiology | www.frontiersin.org 7 October 2021 | Volume 12 | Article 744632