cb99e42774494fa92caa081ac5388c48 pmc_10417281.pdf 57d844b041c6990f8d0f24d9f0fa7b53c39fad6a pmc_10417281.pdf 68987557012700a926cd92ff6ad39ff11a54e2eb5cf19691287db8208b111157 pmc_10417281.pdf Title: Metabolic Pathway Modeling in Muscle of Male Marathon Mice (DUhTP) and Controls (DUC)—A Possible Role of Lactate Dehydrogenase in Metabolic Flexibility Subject: In contracting muscles, carbohydrates and fatty acids serve as energy substrates; the predominant utilization depends on the workload. Here, we investigated the contribution of non-mitochondrial and mitochondrial metabolic pathways in response to repeated training in a polygenic, paternally selected marathon mouse model (DUhTP), characterized by exceptional running performance and an unselected control (DUC), with both lines descended from the same genetic background. Both lines underwent three weeks of high-speed treadmill training or were sedentary. Both lines’ muscles and plasma were analyzed. Muscle RNA was sequenced, and KEGG pathway analysis was performed. Analyses of muscle revealed no significant selection-related differences in muscle structure. However, in response to physical exercise, glucose and fatty acid oxidation were stimulated, lactate dehydrogenase activity was reduced, and lactate formation was inhibited in the marathon mice compared with trained control mice. The lack of lactate formation in response to exercise appears to be associated with increased lipid mobilization from peripheral adipose tissue in DUhTP mice, suggesting a specific benefit of lactate avoidance. Thus, results from the analysis of muscle metabolism in born marathon mice, shaped by 35 years (140 generations) of phenotype selection for superior running performance, suggest increased metabolic flexibility in male marathon mice toward lipid catabolism regulated by lactate dehydrogenase. Keywords: glycogen; lactate; pathway analysis; skeletal muscle; treadmill training Author: Julia Brenmoehl, Elli Brosig, Nares Trakooljul, Christina Walz, Daniela Ohde, Antonia Noce, Michael Walz, Martina Langhammer, Stefan Petkov, Monika Röntgen, Steffen Maak, Christina E. Galuska, Beate Fuchs, Björn Kuhla, Siriluck Ponsuksili, Klaus Wimmers and Andreas Hoeflich Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jul 25 09:27:15 2023 CEST ModDate: Tue Jul 25 09:39:12 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2177469 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- RREXSY+VnURWPalladioL Type 1 Custom yes yes no 10 0 RBETNG+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 WMMJWY+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 CCEUGZ+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 PFKOHU+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 42 0 FGLHJM+CMSY10 Type 1 Builtin yes yes no 67 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 74 0 MPUDFL+PazoMath Type 1 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BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 313 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-09-01 08:22:15 CEST RepresentationInformation: pmc_10417281.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-07-12 02:35:42 CEST Size: 2177469 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 567 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Animals and Experimental Design and Sample Collection Destination: subsection.2.1 Item: Title: Immunohistochemical Evaluation of Musculus rectus femoris Destination: subsection.2.2 Item: Title: RNA Isolation, Next-Generation Sequencing (NGS), and Differential Gene Expression Analysis Destination: subsection.2.3 Item: Title: Validation by Fluidigm Destination: subsection.2.4 Item: Title: Pathway Analysis Destination: subsection.2.5 Item: Title: Determination of Enzyme Activities Destination: subsection.2.6 Item: Title: Determination of Plasma Glucose, Insulin, and Lactate Destination: subsection.2.7 Item: Title: Untargeted LC-MS/MS Analysis of Lipids and Fatty Acids in Serum Destination: subsection.2.8 Item: Title: Determination of Muscular Glycogen Content Destination: subsection.2.9 Item: Title: Statistical Analysis Destination: subsection.2.10 Item: Title: Results Destination: section.3 Children: Item: Title: Reduced Body and Muscle Weight in Response to Selection and Training in Marathon Mice Destination: subsection.3.1 Item: Title: Analysis of mRNA Indicates Induction of Glycolysis, Beta-Oxidation, TCA-Cycle, and Oxidative Phosphorylation in Muscles from DUhTP Mice Destination: subsection.3.2 Item: Title: Plasma Levels of Energy Metabolites in Response to Phenotype Selection and Physical Activity Destination: subsection.3.3 Item: Title: Treadmill Running Results in Higher Glycogen Levels and Reduced Lactate Dehydrogenase Activity in Muscle from DUhTP Mice Destination: subsection.3.4 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Metabolic Pathway Modeling in Muscle of Male Marathon Mice (DUhTP) and Controls (DUC) A Possible Role of Lactate Dehydrogenase in Metabolic Flexibility Author: Julia Brenmoehl, Elli Brosig, Nares Trakooljul, Christina Walz, Daniela Ohde, Antonia Noce, Michael Walz, Martina Langhammer, Stefan Petkov, Monika Röntgen, Steffen Maak, Christina E. Galuska, Beate Fuchs, Björn Kuhla, Siriluck Ponsuksili, Klaus Wimmers and Andreas Hoeflich Subject: In contracting muscles, carbohydrates and fatty acids serve as energy substrates; the predominant utilization depends on the workload. Here, we investigated the contribution of non-mitochondrial and mitochondrial metabolic pathways in response to repeated training in a polygenic, paternally selected marathon mouse model (DUhTP), characterized by exceptional running performance and an unselected control (DUC), with both lines descended from the same genetic background. Both lines underwent three weeks of high-speed treadmill training or were sedentary. Both lines’ muscles and plasma were analyzed. Muscle RNA was sequenced, and KEGG pathway analysis was performed. Analyses of muscle revealed no significant selection-related differences in muscle structure. However, in response to physical exercise, glucose and fatty acid oxidation were stimulated, lactate dehydrogenase activity was reduced, and lactate formation was inhibited in the marathon mice compared with trained control mice. The lack of lactate formation in response to exercise appears to be associated with increased lipid mobilization from peripheral adipose tissue in DUhTP mice, suggesting a specific benefit of lactate avoidance. Thus, results from the analysis of muscle metabolism in born marathon mice, shaped by 35 years (140 generations) of phenotype selection for superior running performance, suggest increased metabolic flexibility in male marathon mice toward lipid catabolism regulated by lactate dehydrogenase. 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