Musde Passive Stretch-Induced Activation of Skeletal Muscle Satellite Cells

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Satellite cells are normally quiescent in adult muscle, but they can be responsible for regeneration and work-induced hypertrophy of muscle fibers. Of all the growth factors studies thus far, only hepatocyte growth factor (HGF) has been shown to stimulate quiescent satellite cells to enter the cell cycle (Alien et al., 1995; Tatsumi et al., 1998). HGF protein was localized in the extracellular matrix of uninjured skeletal muscle fibers and shown to be the active agent in a crushed muscle extract. The signaling receptor for HGF is the c-met proto-oncogene, and its message and protein have been found in quiescent satellite cells (Alien et al., 1995; Cornelison ＆ Wold, 1997; Tatsumi et al., 1998). Therefore, a critical aspect of the activation of quiescent satellite cells may be the release of active HGF from its sequestration and presentation to the c- met. The purpose of this study was to determine whether satellite cells could be activated by mechanical stretch in vivo, and to explore … More the possible role of HGF in the activation mechanism.Stretch experiments were conducted in the living animal using our suspension model, which used the weight of the hind portion of 9-month-old S. D. rats to stretch the adductor and gracilis muscles on the inside of the left hind limb suspended for a period of 0.5-2.0 hr. At the end of the stretch period, rats received an ip-injection of BrdU; 16 hr later satellite cells were prepared (>97 % desmin-positive) followed by immunocytochemistry for BrdU at 30 hr post-plating. Depending on the period of stretch, BrdU-labeling and cell yield were increased two and four-fold, respectively, over the contralateral un-stretched leg or control muscle from untreated rats. Also, stretched muscle extract (SME), which was prepared from the 2 hr-stretched tissue by incubating it in PBS, showed active HGF as revealed by immunoblotting, and could activate satellite cells in culture in a dose-dependent manner; the activity of 0.5 mg SME/ml was comparable to that of exogenous HGF and could be neutralized by anti-HGF antibody. Un-stretched muscle extract did not show activating activity. These experiments provide a critical link between mechanical perturbation of skeletal muscle and biochemical signals that result in entry of satellite cells into the cell cycle. At this time, the mechanism of HGF release from muscle fibers has not been established, awaiting further studies. Less