The major goal of this unit is to perturb and investigate the role of a number of intrinsic properties of muscle that may contribute to the progressive loss of force generating capacity and endurance that occurs in aging. Particular attention is focused on the selective loss of large diameter, high power output fibers. The long-term goal is to gain the understanding tools necessary to moderate the loss of strength and endurance in the skeletal musculature that accompanies human senescence. The susceptibility of mouse skeletal muscle to contraction-induced injury in senescence will be examined and contrasted with the susceptibility to injury in youth. A large component of contraction-induced injury is due to damage associated with oxygen free radical production. The extent of this type of damage likely increases with aging. We will engineer transgenic mice that overexpress antioxidant enzymes in the skeletal muscle, in an attempt to protect the muscle from free radical damage. We will then assess a viral gene delivery system that can be used to specifically transfer antioxidant enzyme genes to injured skeletal muscle. The effect of either altering the cross-sectional area or reducing force per cross- sectional area of type IIb and IIWx fibers on the susceptibility to contraction-induced injury will be examined. Finally, given that a similar pattern of fiber type of chronic myopathies, we will characterize the adaptive response to functional deficits in different fiber types.
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