Pathogenesis of Duchenne muscular dystrophy: The calcium hypothesis revisited

Abstract

Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium-ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis.

Tropomodulin Capping of Actin Filaments in Striated Muscle Development and Physiology

“…Furthermore, whether Tmod3 plays a role in the cardiac SR analogous to its role in the skeletal muscle SR remains to be determined. It is tempting to speculate that the upregulation of γ -actin that occurs in muscular dystrophy might influence Ca 2+ handling in the SR in addition to its better-characterized role in binding to dystrophin and mechanically fortifying the sarcolemma; such a model would be consistent with evidence implicating aberrant SR Ca 2+ handling in the pathogenesis of muscular dystrophy [137–139]. …”

“…Indeed, γ -actin upregulation without compensatory alterations in the pool of γ -actin-regulatory proteins may result in uncontrolled γ -actin polymerization, which may adversely affect the structure, stability, and function of the SR and/or sarcolemma. Another possibility is that muscular dystrophy-induced misregulation of γ -actin-regulatory proteins may alter γ -actin turnover in a manner that is toxic to the muscle cell via mechanisms involving aberrant Ca 2+ handling [137, 138]. It is important to recognize that such proposals are speculative at this point.…”

Factors Associated with Induced Chronic Inflammation in mdx Skeletal Muscle Cause Posttranslational Stabilization and Augmentation of Extrasynaptic Sarcolemmal Utrophin

“…Necrosis and regeneration of muscle fibers, as well as increased serum creatine kinase activity, are hallmarks of DMD. Necrosis is believed to be triggered by calcium influx into muscle fibers (McDouall et al, 1990;Tay et al, 1992;Porter et al, 2002) and to a lesser extent some cytotoxic T cells (Fang et al, 2000;Porter et al, 2003).…”

Muscle biopsy and muscle fiber hypercontraction: a brief review

“…As noted above, hypercontracted ®bers are typically not present in muscle samples obtained by open biopsy from healthy individuals (Meltzer et al 1976;Moulds et al 1977;Schmalbruch 1973Schmalbruch , 1975. A high [Ca 2+ ] has been implicated in the hypercontraction and degeneration noted in diseased skeletal muscle (Oberc and Engel 1977;Schmalbruch 1975;Tay et al 1992). For example, Oberc and Engel (1977) suggested that a breach in the sarcolemma of a muscle ®ber would result in Ca 2+ in¯ux, leading to contraction and eventual degradation of muscle proteins and phospholipids.…”

“…For example, Oberc and Engel (1977) suggested that a breach in the sarcolemma of a muscle ®ber would result in Ca 2+ in¯ux, leading to contraction and eventual degradation of muscle proteins and phospholipids. Similarly, Tay et al (1992) suggested that dystrophin de®ciency results in localized failures of Ca 2+ -ATPase activity, thus resulting in intracellular Ca 2+ accumulation, leading to hypercontraction and eventual rupture of the sarcolemma, and eventually resulting in cell necrosis.…”