Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy

Abstract

Muscular dystrophy (MD) refers to a clinically and genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. Although the primary defect underlying most forms of MD typically results from a loss of sarcolemmal integrity, the secondary molecular mechanisms leading to muscle degeneration and myofiber necrosis is debated. One hypothesis suggests that elevated or dysregulated cytosolic calcium is the common transducing event, resulting in myofiber necrosis in MD. Previous measurements of resting calcium levels in myofibers from dystrophic animal models or humans produced equivocal results. However, recent studies in genetically altered mouse models have largely solidified the calcium hypothesis of MD, such that models with artificially elevated calcium in skeletal muscle manifest fulminant dystrophic-like disease, whereas models with enhanced calcium clearance or inhibited calcium influx are resistant to myofiber death and MD. Here, we will review the field and the recent cadre of data from genetically altered mouse models, which we propose have collectively mostly proven the hypothesis that calcium is the primary effector of myofiber necrosis in MD. This new consensus on calcium should guide future selection of drugs to be evaluated in clinical trials as well as gene therapy-based approaches.

Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis

“…[15] and that mdx myofibers show discrete elevated basal intracellular free Ca 2? levels [31]. Thus, in concordance with the elevated hemichannels activity found in mdx myofibers, we also detected an elevated basal intracellular free Ca 2?…”

Leaky ryanodine receptors delay the activation of store overload-induced Ca2+ release, a mechanism underlying malignant hyperthermia-like events in dystrophic muscle

“…Regardless RyRs clusters acting in concert must drive these events (43). As Ca 2ϩ sparks in mammalian skeletal muscle occur in the presence of a reduced inhibition of the RyRs cytoplasmic sites, and thus also a lowered threshold for SOICR (5,15,16), we suggest the discrete Ca 2ϩ release events observed here, and in other studies of mammalian skeletal muscle (18,32,42,43), are discrete SOICR events. That is, they activate where the local [Ca 2ϩ ] SR is high and there is a stochastic activation of a number of RyRs in a cluster that breach the threshold for event occurrence.…”

“…However, increases in resting cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ] cyto ) that must underlie such events suggest some dysfunction of the Ca 2ϩ -handling apparatus within the muscle as a result of exposure to agents used in surgery. In DMD the occurrence of MH-like events is not surprising as changes in Ca 2ϩ homeostasis are known to affect muscle pathology (5).…”

“…The proteins that have been implicated in the changes in Ca 2ϩ homeostasis in mdx muscle are stretch-activated channels (2) on the plasma membrane; the ryanodine receptor (RyR) on the SR membrane (3); and the store-operated Ca 2ϩ entry (SOCE) mechanism that is dependent on depletions in SR Ca 2ϩ concentration ([Ca 2ϩ ] SR ), among other pathways (5). We note that SOCE is dependent on [Ca 2ϩ ] SR and has been demonstrated to rapidly activate and deactivate in response to changes in [Ca 2ϩ ] SR in mdx muscle and so should not be considered dysfunctional (11).…”

Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

“…Cytosolic calcium overload is a pivotal pathogenic event leading to muscle damage and force reduction in DMD 156 . Restoring calcium homeostasis holds great promise for treating Duchenne cardiomyopathy.…”