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

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.