The purpose is to investigate the function of dystrophin and the dystrophin-associated proteins (DAPs) in skeletal muscle fibers and how defects in the dystrophin-DAP complex contribute to the pathological changes in muscle over the life span of mdx mice. The absence of dystrophin from the muscles of patients with Duchenne muscular dystrophy leads to ongoing muscle fiber degeneration, progressive necrosis, and fibrosis. Dystrophin is also absent from the muscles of mdx mice. The mechanisms underlying the degenerative process in dystrophic muscle are unknown, but replacement of dystrophin in transgenic-mdx mice prevents many of the dystrophic symptoms. In control animals, degeneration of myofibers may result from contraction-induced injury and susceptibility to contraction-induced injury than those in age-matched control mice, but for muscles in transgenic-mdx mice the susceptibility to injury is not known, nor has the effect of age on contraction-induced injury been studied in mdx or transgenic mdx-mice. The working hypothesis are that (i) the dystrophin-DAP complex shunts contractile forces laterally from the myofibrils through the plasma membrane to the extracellular matrix, and a lack of dystrophin results in stress concentrations on the sarcolemma which damage the membrane, and a mechanically compromised cytoskeleton which increases sarcomere heterogeneity and damage; and (ii) the increased susceptibility to both sarcolemma and sarcomere damage is aggravated as animals age. Specific hypotheses have been formulated regarding the mechanical function of dystrophin and the effects of age on contraction- induced injury of dystrophic muscle fibers. Structure/function relationships of the dystrophin-DAP complex will be studied in single intact fibers from muscles of control, mdx, and transgenic-mdx mice, and contraction-induced injury will be studied using single fibers in vitro and whole muscles in situ from adult and old mice. Determining the function of dystrophin and why its absence is so devastating will contribute significantly to out understanding of the mechanisms underlying the wasting and weakness that occurs with dystrophy and with normal aging.
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