Adult skeletal muscle has the striking ability to repair and regenerate itself after injury. This would not be possible without satellite cells, a subpopulation of cells existing at the margin of the myofiber. Under most conditions, satellite cells are quiescent, but they are activated in response to trauma, enabling them to guide skeletal muscle regeneration. In degenerative skeletal muscle states, including motor nerve denervation, advanced age, atrophy secondary to deconditioning or immobilization, and Duchenne muscular dystrophy, satellite cell numbers and proliferative potential significantly decrease, contributing to a diminution of skeletal muscle's regenerative capacity and contractility. This review will highlight the fate of satellite cells in several degenerative conditions involving skeletal muscle, and will attempt to gauge the relative contributions of apoptosis, senescence, impaired proliferative potential, and host factors to satellite cell dysfunction.

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Peripheral motor nerve trauma severely compromises skeletal muscle contractile function. Satellite cells respond to denervation by dividing multiple times, ultimately fusing with other satellite cells or myocytes to form new muscle fibers. After chronic denervation, satellite cell numbers decline dramatically, impairing the ability to regenerate and repair myofibers. This satellite cell depletion may contribute to the mechanical deficit observed in denervated or reinnervated muscle. Apoptosis, an evolutionarily conserved form of cell suicide, is a potential mechanism for satellite cell depletion in denervated skeletal muscle. This work tested the hypothesis that skeletal muscle denervation increases satellite cell susceptibility to apoptotic cell death. Adult rats underwent sciatic nerve transection to denervate the distal hindlimb musculature; rats of similar age without the operation served as controls. Two, 6, 10, or 20 weeks after denervation (n = 6 each group), the gastrocnemius and soleus were excised, enzymatically digested, and plated for satellite cell culture. After reaching 95 percent confluence, satellite cells were treated for 24 hours with tumor necrosis factor-alpha (20 ng/ml) and actinomycin D (250 ng/ml), known pro-apoptotic agents. Immunostaining for activated caspases, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and hematoxylin and eosin staining were performed to identify apoptotic satellite cells. Percentages of apoptotic cells were quantified histomorphometrically. In addition, the presence or absence of bcl-2 and bax was determined by Western blot analysis of control, 6 weeks of denervation, and 10 weeks of denervation specimens. At 6 and 10 weeks after nerve transection, TUNEL and caspase activity were increased more than two-fold in satellite cells isolated from denervated muscle compared with those isolated from control muscle (p < 0.05). In all experimental groups, retention of adherence to the collagen-coated substrate was strongly associated with satellite cell survival. Western blot analysis revealed that adherent satellite cells from all groups expressed both bcl-2 and bax. These data support the authors' hypothesis that skeletal muscle denervation increases satellite cell susceptibility to apoptotic cell death. Apoptosis may play a causative role in the depletion of satellite cells in long-term denervated skeletal muscle.