Cross-bridge mechanisms of muscle weakness in multiple sclerosis.

Vastus lateralis muscle biopsies were obtained from six individuals with multiple sclerosis (MS) having an Expanded Disability Status Score of 4.75 +/- 0.28, and from six age- and gender-matched individuals without MS. Biopsies from the MS group showed fewer fibers (31 +/- 4 vs. 46 +/- 4%) containing the type IIa myosin heavy chain (MHC) isoform exclusively. However, the percentage of fibers coexpressing type IIa and IIx MHC increased in direct proportion with MS disability status. The average unloaded shortening velocity of skinned fibers containing type I or IIa MHC did not differ between subject groups. Peak Ca(2+)-activated force was 11-13% lower in fibers from the MS group due to atrophy (type I and IIa fibers) and reduced specific force (type I fibers). Increasing intracellular inorganic phosphate (0-30 mM) or hydrogen ion (pH 7.0-6.2) reduced Ca(2+)-activated force in a manner that was independent of MS status. Thus, fibers from the MS group showed a subtle shift in fast MHC isoform coexpression and a modest reduction in cross-bridge number, density, or average force, with no change in maximal cross-bridge cycling rate or susceptibility to intracellular metabolites. These changes explain part of the muscle weakness and fatigue experienced by individuals with MS.