Graduate Thesis Or Dissertation
 

Cellular mechanisms of muscle weakness and fatigability in individuals with multiple sclerosis

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/n296x230b

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  • Muscle weakness and fatigue are debilitating symptoms of multiple sclerosis (MS). Approximately 50% of muscle weakness and fatigue have been attributed to deficits within the peripheral nervous system, specifically mechanisms residing in the muscle. The goals of this study were to identify the cellular mechanisms of contraction within the muscle cell, which could contribute to the muscle weakness and fatigue in MS. Whole muscle assessment of knee extensor strength revealed that subjects with MS (N=6) were 48% weaker than subjects without MS (N=6). Pedometer results revealed that MS subjects were 68% less active on a daily basis than controls. Using an in vitro single fiber preparation obtained from the vastus lateralis, cross-bridge mechanisms of contraction were tested to understand their role in muscle weakness and fatigue. Peak Ca⁺²-activated force was 13-44% lower (p<0.05) in type I, I/IIa, IIa/IIx, IIx fibers from MS subjects. The force deficit was attributed to the 14-32% smaller (p<0.05) cross-sectional area (CSA) of type I, I/IIa, IIa, IIx fibers and to a 6% lower specific force (p<0.05) in type I fibers from MS subjects. While there were no differences found between groups for fiber unloaded shortening velocity, peak absolute power in type I fibers was 11% lower (p<0.05) in MS subjects. Skinned fiber preparations were also used to test peak Ca⁺²-activated force at varying concentrations (0-30 mM) of inorganic phosphate (Pi) and at different pH (6.2-7.0). Force declined with increases in Pi concentrations, with a greater reduction of force in type I fibers (66%) versus type ha fibers (40%) at 30 mM (p<0.05). In contrast, reductions in force at pH 6.5 (17%) and 6.2 (24%) were similar for type I and IIa fibers. Assessment of the myosin heavy chains (MHC) revealed that MS subjects had 33% fewer type ha fiber than controls, and there was a trend towards increased numbers of type IIa/IIx and IIx fibers in MS subjects. The results of this study revealed that a portion of the muscle weakness in individuals with MS is due to deficits at the level of the muscle cell and cross-bridge.
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