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Metabolic and Skeletal Muscle Dysfunctions Correlate with Fatigue-Like Behavior in an Animal Model of Multiple Sclerosis

ABSTRACT: Multiple sclerosis associated fatigue (MS fatigue) is one of the most common and troubling symptoms experienced by people with MS, but the cause of MS fatigue remains unknown. The nature of cognitive and physical exhaustion suggests that MS fatigue can be a metabolic disease that impacts energy demanding processes such as neuronal activity and skeletal muscle contraction. In this study, we investigated how autoimmune-mediated inflammation causes skeletal muscle atrophy and metabolic dysfunctions, which may contribute to MS fatigue. Using a relapsing-remitting model experimental autoimmune encephalomyelitis (EAE), we found that disease manifestations substantially altered the metabolic activities of the mice over time. EAE decreased muscle mass and force input in both fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles but only increased the rate of fatigue in EDL muscle. Gene expression analysis of EDL muscle shows that genes related to cellular respiration and mitochondrial functions were significantly down regulated during when EAE manifestations were the most severe, but this genotype was reversed during disease remission. In addition, EAE-induced mice showed fatigue-like behavior during treadmill test. Surprisingly, this fatigue-like behavior was also observed with mice immunized with a CNS non-specific antigen, suggesting the contributions of the central nervous system-independent immune activation. To our knowledge, this is the first report to characterize skeletal muscle properties and fatigue-like behavior in mice following EAE induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE326115 | GEO | 2026/08/05

REPOSITORIES: GEO

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Project description:This a model from the article: A mathematical model of fatigue in skeletal muscle force contraction. Shorten PR, O'Callaghan P, Davidson JB, Soboleva TK. J Muscle Res Cell Motil 2007;28(6):293-313 18080210 , Abstract: The ability for muscle to repeatedly generate force is limited by fatigue. The cellular mechanisms behind muscle fatigue are complex and potentially include breakdown at many points along the excitation-contraction pathway. In this paper we construct a mathematical model of the skeletal muscle excitation-contraction pathway based on the cellular biochemical events that link excitation to contraction. The model includes descriptions of membrane voltage, calcium cycling and crossbridge dynamics and was parameterised and validated using the response characteristics of mouse skeletal muscle to a range of electrical stimuli. This model was used to uncover the complexities of skeletal muscle fatigue. We also parameterised our model to describe force kinetics in fast and slow twitch fibre types, which have a number of biochemical and biophysical differences. How these differences interact to generate different force/fatigue responses in fast- and slow- twitch fibres is not well understood and we used our modelling approach to bring new insights to this relationship. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Shorten PR, O'Callaghan P, Davidson JB, Soboleva TK. (2007) - version02 This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Abstract Background Sarcopenia is a major contributor to frailty and mortality in aging and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear. Methods Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)–induced obesity for six weeks and to naturally aged (18-month-old) male mice for 12 weeks. Skeletal muscle fiber morphology and transcriptomic profiles were analyzed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed. Results Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibers in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, P < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62 to -79%, P < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28 to -72%, P < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fiber size (+14%, P < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27 to -82%, P < 0.05 vs. aged controls). Conclusions Imeglimin attenuates skeletal muscle atrophy in obesity and aging, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programs. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.

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Metabolic and Skeletal Muscle Dysfunctions Correlate with Fatigue-Like Behavior in an Animal Model of Multiple Sclerosis

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