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

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 Ca2+ release is altered in mdx fibres. Action potential-evoked Ca2+-dependent fluorescence transients were recorded, using both low and high affinity Ca2+ 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 Ca2+ transients was significantly decreased in mdx mice with no measured difference in that of the surface action potential. In addition, Ca2+ 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 Ca2+ release flux is responsible for the decrease in the peak of the Ca2+ transient in mdx fibres. Since the myoplasmic Ca2+ 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.