Aged muscle displays decreased skeletal muscle regenerative capacity after injury. A progressive decline in muscle strength with age contributes to impaired ftmctional mobility, and muscle weakness has been associated with increased likelihood for falls [4]). Increasing age typically results in a decreased overall skeletal muscle regeneration in response to injury [5-7], which further contributes to the decreased muscle mass and weakness [5], increased susceptibility to recurrent muscle injury [8;9], and prolonged recovery [io;ii]. Aging skeletal muscle demonstrates a shift from functional myofiber repair, as is typically seen in young individuals, to a """"""""quick-fix"""""""" default towards fibrosis formation. Fibrosis formation after injury has been associated with muscle weakness [12] and an increased injury recurrence [13]. Muscle precursor cells (MPCs), those cells predominantly responsible for skeletal muscle regeneration, demonstrate an increased myogenic-to-fibrogenic conversion in aged muscle [2]. This conversion entails a shift in the resident cell's ability to restore the original function and structure of expired cells. Following injury, MPCs appear to largely differentiate into fibrosis precursor cells, fibroblasts. Recent findings from our laboratory have demonstrated that fibrosis formation after injury is significantly and inversely correlated with skeletal muscle vascularity [14]. Moreover, a significant decrease in the number of MPCs is concomitant with. increasing age [15-17], a decrease that may be related to a reduced vascular supply of aged skeletal muscle. MPC numbers in human skeletal muscle have been shown to correlate linearly with vascularity, and MPC niches were found to be juxtavascular and non-randomly associated with capillary localization [18]. Accordingly, myopathies resulting in decreased vascularity were shown to be associated with a proportionate decrease in MPCs [18]. Myogenic-to-fibrogenic conversion also appears to be related to the muscle vascular supply, and in vitro heterochronic studies, in which MPCs isolated from aged animals are exposed to """"""""young"""""""" serum demonstrate significantly increased myogenicity and a decreased fibrotic conversion [3:19]. These findings suggest that the age-related decline in MPC myogenicity is reversible, and intrinsic factors controlling MPC fate are responsive to extrinsic stimuli [3].
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