Role of mechanosensitive channels in skeletal muscle damage and muscular dystrophy

D.G. Allen, Physiology, University of Sydney, Camperdown, NSW, Australia

Muscles which are stretched during contraction are liable to a mild form of muscle damage including immediate weakness and delayed stiffness, soreness and swelling. In muscular dystrophy, which is characterized by profound muscle degeneration, stretch-induced damage is more severe and recovery incomplete. We have studied the mechanisms involved by measuring ionic changes in single fibres following a short series of stretched contractions. Intracellular sodium shows a slow increase after stretched contractions, not seen after isometric contractions, which can be prevented by either Gd³⁺ or streptomycin (Yeung et al., 2003) . Both Gd³⁺ and streptomycin block a class of mechanosensitive channels (MSCs), permeable to both Na⁺ and K⁺>, present in mammalian muscle fibres (Franco-Obregon & Lansman, 2002) . In mdx mice, which lack dystrophin, muscles showed an increased resting [Na⁺]_i and a greater increase in [Na⁺]_i following stretched contractions which was also blocked by the above agents. We have previously shown that stretched contraction increase resting [Ca²⁺]_i but reduced tetanic [Ca²⁺]_i (Balnave & Allen, 1995) . Recently we found that Gd³⁺, streptomycin or a potent blocker of MSCs, GsMTx4, could prevent the rise in resting [Ca²⁺]_i and simultaneously increased the tetanic [Ca²⁺]_i from the reduced level observed after stretched contractions. In both wild-type and mdx muscles the reduced force following stretched contractions was partly reversed by MSC blockers, presumably as a consequence of the increased tetanic [Ca²⁺]_i noted above.

These data suggest that MSCs are present in both wild-type and mdx muscle and are persistently opened by stretched contractions. The subsequent entry of Na⁺ and Ca²⁺ may have roles in the reduced force and perhaps other aspects of muscle damage.

(1) Balnave CD & Allen DG (1995). Intracellular calcium and force in single mouse muscle fibres following repeated contractions with stretch. J Physiol 488, 25-36.

(2) Franco-Obregon A & Lansman JB (2002). Changes in mechanosensitive channel activity following mechanical stimulation in skeletal muscle myotubes from the mdx mouse. J Physiol 539, 391-407.

(3) Yeung EW, Head SI & Allen DG (2003). Gadolinium reduces short-term stretch-induced muscle damage in isolated mdx mouse muscle fibres. J Physiol 552, 449-458.