Mammalian skeletal muscle undergoes profound atrophy after denervation. The functional restoration of denervated muscle is a significant clinical problem, and the success of restorative attempts decreases substantially after several months of denervation. Rat extensor digitorum longus muscles are capable of excellent restoration for the first 2-3 months after denervation, but after that time the level of restoration upon reinnervation decreases dramatically. Severe atrophy precedes the loss of restorative capacity. Attempts to understand the basis for the reduced restorative ability have led to an intensive analysis of the biology of long-term denervated muscle. In fast muscles, the satellite cell population undergoes a major increase over the first 2 months after denervation, and thereafter it steadily declines. Atrophying muscle fibers lose nuclei through apoptosis, and some degenerate. New muscle fibers form either alongside atrophying muscle fibers or in place of degenerated ones. The microcirculation undergoes a tenfold diminution over the first year after denervation, and over time denervated muscle is characterized by increasing amounts of interstitial collagen. Various barriers to reinnervation are discussed. Attempts to improve the restoration of long-term denervated muscle have included the stimulation of regeneration and removal of interstitial collagen. Both of these have resulted in significant improvement in the level of functional restoration. Although chronic electrical stimulation maintains an excellent degree of mass and force in a denervated muscle, grafts of such muscles undergo no better restoration than grafts of denervated muscles.
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