Molecular and cellular contractile dysfunction of dystrophic muscle from young mice. Muscle Nerve 34

ABSTRACT: The purpose of this study was to determine whether contrac-tile protein alterations are responsible for force deficits in young dystrophic muscle. Contractility of intact extensor digitorum longus muscles and per-meabilized fibers from wild-type (wt), dystrophin-deficient (mdx), and dys-trophin/utrophin-deficient (mdx:utrn/) mice aged 21 and 35 days was determined. Myosin structural dynamics were assessed by site-directed spin labeling and electron paramagnetic resonance spectroscopy. The principal finding was that force generation was depressed by 20 % in mdx muscles, but fiber Ca2-activated force and myosin structure were not different from wt animals, suggesting that contractile proteins are not responsible for the force deficits in those muscles. For mdx:utrn/ mice, muscle and fiber forces were 40 % lower than wt and the fraction of strong-binding myosin during contraction was reduced by 13%. These data indicate that contractile protein alterations, in addition to myosin dysfunction, cause force deficit in muscles from young mdx:utrn/ mice. Elucidating the molecular mecha-nisms underlying muscle weakness at the onset of disease is important for designing treatment strategies