Cellular and molecular responses to increased skeletal muscle loading after irradiation

Abstract

. Cellular and molecular responses to increased skeletal muscle loading after irradiation. Am J Physiol Cell Physiol 283: C1182-C1195, 2002. First published June 26, 2002 10.1152/ajpcell.00173.2002Irradiation of rat skeletal muscles before increased loading has been shown to prevent compensatory hypertrophy for periods of up to 4 wk, possibly by preventing satellite cells from proliferating and providing new myonuclei. Recent work suggested that stem cell populations exist that might allow irradiated muscles to eventually hypertrophy over time. We report that irradiation essentially prevented hypertrophy in rat muscles subjected to 3 mo of functional overload (OL-Ir). The time course and magnitude of changes in cellular and molecular markers of anabolic and myogenic responses were similar in the OL-Ir and the contralateral nonirradiated, overloaded (OL) muscles for the first 3-7 days. These markers then returned to control levels in OL-Ir muscles while remaining elevated in OL muscles. The number of myonuclei and amount of DNA were increased markedly in OL but not OL-Ir muscles. Thus it appears that stem cells were not added to the irradiated muscles in this time period. These data are consistent with the theory that the addition of new myonuclei may be required for compensatory hypertrophy in the rat. myonuclei; satellite cell MATURE MAMMALIAN SKELETAL muscle cells are multinucleated myofibers that are formed via the fusion of individual myoblast cells during development. Evidence suggests that these multinucleated myofibers are permanently differentiated and therefore incapable of mitotic activity (8,21,54). During muscle regeneration after injury, myofibers can be repaired and/or replaced via the fusion of muscle stem cells (satellite cells) either with existing damaged myofibers or with each other to form new myofibers (43,48,49).The impetus for much of the current interest in the role of satellite cells in muscle adaptation has its roots in the muscle regeneration literature. The results from a number of studies using muscle injury models indicated that relatively modest doses of radiation, well below the threshold of those required to induce overt cellular injury in vivo, interfered with the regeneration of skeletal muscle (see, e.g., Refs. 15, 25, 32). Because there is an absence of overt cellular damage, it was postulated that the failure of myofibers to regenerate resulted from damage to DNA that prevents satellite cell proliferation. It would follow then that mature, permanently differentiated mammalian myofibers would not appear to be the locus of the radiationinduced mitotic failure (8,54). Thus the inhibitory effects of radiation on muscle regeneration were proposed to be a result of the incapacitation of satellite cell mitotic activity.The theory that radiation-induced inhibition of cellular proliferation can inhibit mammalian muscle adaptation and repair has recently been extended to include the prevention of compensatory muscle hypertrophy after increased loading. In support of this theory, a nu...

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