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Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss havpredominantly focused on [...]

The tumor necrosis factor-[alpha] (TNF[alpha])-mediated inhibition of myogenic differentiation is found to be dependent on p53 through a PW1-mediated pathway. The p53 plays a novel role in mediating muscle stem cell behavior and muscle atrophy, and has pointed towards new targets for the therapeutic treatment of muscle wasting (cachexia).

Cytoplasmic [Ca.sup.2+] concentration ([[Ca.sup.2+]].sub.i]) variation is a key event in myoblast differentiation, but the mechanism by which it occurs is still debated. Here we show that increases of extracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.o]) produced membrane hyperpolarization and a concentration-dependent increase of [[[Ca.sup.2+]].sub.i] due to [Ca.sup.2+] influx across the plasma membrane. Responses were not related to inositol phosphate turnover and [Ca.sup.2+]-sensing receptor. [[[Ca.sup.2+]].sub.o]-induced [[[Ca.sup.2+]].sub.i] increase was inhibited by [Ca.sup.2+] channel inhibitors and appeared to be modulated by several kinase activities. [[[Ca.sup.2+]].sub.i] increase was potentiated by depletion of intracellular [Ca.sup.2+] stores and depressed by inactivation of the [Na.sup.+]/[Ca.sup.2+] exchanger. The response to arginine vasopressin (AVP), which induces inositol 1,4,5-trisphosphate-dependent [[[Ca.sup.2+]].sub.i] increase in L6-C5 cells, was not modified by high [[[Ca.sup.2+]].sub.o]. On the contrary, AVP potentiated the [[[Ca.sup.2+]].sub.i] increase in the presence of elevated [[[Ca.sup.2+]].sub.o]. Other clones of the L6 line as well as the rhabdomyosarcoma RD cell line and the satellite cell-derived C2-C12 line expressed similar responses to high [[[Ca.sup.2+]].sub.o], and the amplitude of the responses was correlated with the myogenic potential of the cells. calcium; myogenesis; calcium channels; sodium-calcium exchanger