Calcium entry through stretch-inactivated ion channels in mdx myotubes

Abstract

Recent advances in understanding the molecular basis of human X-linked muscular dystrophies have come from the identification of dystrophin, a cytoskeletal protein associated with the surface membrane. Although there is little or virtually no dystrophin in affected individuals, it is not known how this causes muscle degeneration. One possibility is that the membrane of dystrophic muscle is weakened and becomes leaky to Ca2+. In muscle from mdx mice, an animal model of the human disease, intracellular Ca2+ is elevated and associated with a high rate of protein degradation. The possibility that a lack of dystrophin alters the resting permeability of skeletal muscle to Ca2+ prompted us to compare Ca2(+)-permeable ionic channels in muscle cells from normal and mdx mice. We now show that recordings of single-channel activity from mdx myotubes are dominated by the presence of Ca2(+)-permeable mechano-transducing ion channels. Like similar channels in normal skeletal muscle, they are rarely open at rest, but open when the membrane is stretched by applying suction to the electrode. Other channels in mdx myotubes, however, are often open for extended periods of time at rest and close when suction is applied to the electrode. The results show a novel type of mechano-transducing ion channel in mdx myotubes that could provide a pathway for Ca2+ to leak into the cell.

Alteration in Calcium Handling at the Subcellular Level inmdx Myotubes

“…Changes of Ca 2ϩ channel activities or appearance of novel forms of Ca 2ϩ leak channels, notably of stretch-activated Ca 2ϩ channels, have been reported (18,19). In addition, tetrodotoxin-sensitive spontaneous contractile activity of myotubes in culture exacerbates the stimulated Ca 2ϩ increases (12,13).…”

Modulation by prednisolone of calcium handling in skeletal muscle cells

“…Ca2" entry through leak channels (Fong et al, 1990;Franco & Lansman, 1990) appears to be increased in dystrophin-deficient muscle fibres (Fong et al, 1990) and thereby leads to activation of Ca2"-dependent proteases which in turn would be responsible for muscle necrosis. Therefore, the PDN-induced decrease in Ca2" influx possibly compensates for an enhanced Ca2" entry into dystrophin-deficient cells.…”

“…This increase is localized mainly in areas near the sarcolemma and Ca2+ influx mechanisms would thus be implicated (Turner et al, 1991). An enhancement of the open probability of leak channels (Fong et al, 1990), an activation of stretch-sensitive channels (Franco & Lansman, 1990) and/or a fragile and leaky membrane (Hoffman & Schwartz, 1991) would contribute to this phenomenon. Several authors have proposed a correlation between the increased [Ca2+]i and the enhanced protein degradation found in mdx muscle (Turner et al, 1988;McLennan et al, 1991;Kamper & Rodemann, 1992).…”

Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression

“…In addition, previous studies (Franco Jr. and Lansman, 1990;Turner et al, 1993;Hopf et al, 1996;De Backer et al, 2002;Blake et al, 2002) have demonstrated the high influx of extracellular calcium through a dystrophin-deficient membrane, which may lead to the activation of calpains and subsequent muscle necrosis or apoptosis along with the inflammation response. Thus, to capture the characteristics of each phase, we further focus on mechanisms related to muscle regeneration and calcium homeostasis.…”