The action potential‐evoked sarcoplasmic reticulum calcium release is impaired in mdx mouse muscle fibres

Abstract

The mdx mouse, a model of the human disease Duchenne muscular dystrophy, has skeletal muscle fibres which display incompletely understood impaired contractile function. We explored the possibility that action potential-evoked Ca 2+ release is altered in mdx fibres. Action potential-evoked Ca 2+ -dependent fluorescence transients were recorded, using both low and high affinity Ca 2+ indicators, from enzymatically isolated fibres obtained from extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of normal and mdx mice. Fibres were immobilized using either intracellular EGTA or N -benzyl-p-toluene sulphonamide, an inhibitor of the myosin II ATPase. We found that the amplitude of the action potential-evoked Ca 2+ transients was significantly decreased in mdx mice with no measured difference in that of the surface action potential. In addition, Ca 2+ transients recorded from mdx fibres in the absence of EGTA also displayed a marked prolongation of the slow decay phase. Model simulations of the action potential-evoked transients in the presence of high EGTA concentrations suggest that the reduction in the evoked sarcoplasmic reticulum Ca 2+ release flux is responsible for the decrease in the peak of the Ca 2+ transient in mdx fibres. Since the myoplasmic Ca 2+ concentration is a critical regulator of muscle contraction, these results may help to explain the weakness observed in skeletal muscle fibres from mdx mice and, possibly, Duchenne muscular dystrophy patients.

Ca2+-independent phospholipase A2 enhances store-operated Ca2+ entry in dystrophic skeletal muscle fibers

“…Similar findings have been reported for electrically evoked Ca 2+ transients in mdx FDB fibers, AChevoked Ca 2+ transients in dystrophic myotubes or relaxation speeds after electrical stimulation of dystrophic myotubes (Nicolas-Metral et al, 2001;Rivet-Bastide et al, 1993;Tutdibi et al, 1999;Woods et al, 2004).…”

“…R max was determined by bathing fibers in a 2 mM Ca 2+ containing solution, followed by permeabilization with saponin (100 g/ml). In both cases, fibers were previously incubated for 10 minutes with BTS (50 M), to prevent contraction (Cheung et al, 2002;Woods et al, 2004). R min and R max were not found to be different between C57BL/6J and mdx 5cv FDB fibers.…”

Altered Gene Expression Pathways in Duchenne Muscular Dystrophy

“…Comparisons of the cytosolic calcium transients evoked by single action potential have shown that the calcium transients are reduced in mdx fibers compared with wt fibers (Woods et al 2004;Hollingworth et al 2008). Recently, similar results have been found in fibers from utr -/ -mdx mice (Capote et al 2010).…”

Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle

“…Multiple studies have shown deficits in global EC-coupling in dystrophic muscle fibers (25)(26)(27). These include a significant reduction in the peak amplitude of the Ca 2+ transient and diminished Ca 2+ reuptake into the SR.…”