Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Abstract

There occurs a progressive weakness and wastage of skeletal muscle in different types of muscular dystrophy. The loss of muscle fibers in dystrophic muscle with impaired function is associated with leakage of intracellular enzymes, maldistribution of electrolyte content and metabolic defects in myocytes. Marked increases in the sarcolemma (SL) Na-K ATPase and Ca/Mg-ecto ATPase activities, as well as depressions in the sarcoplasmic reticulum (SR) Ca-uptake and Ca-pump ATPase activities were seen in dystrophic muscles of a hamster model of myopathy. In addition, impaired mitochondrial oxidative phosphorylation and decrease in the high energy stores as a consequence of mitochondrial Ca-overload were observed in these myopathic hamsters. In some forms of muscular dystrophy, it has been shown that deficiency of dystrophin produces marked alterations in the SL permeability and promotes the occurrence of intracellular Ca-overload for inducing metabolic defects, activation of proteases and contractile abnormalities in dystrophic muscle. Increases in SR Ca-release channels, SL Na-Ca exchanger and SL store-operated Ca-channels have been reported to induce Cahandling abnormalities in a mouse model of muscular dystrophy. Furthermore, alterations in lipid metabolism and development of oxidative stress have been suggested as mechanisms for subcellular remodeling and cellular damage in dystrophic muscle. Although, several therapeutic interventions including gene therapy are available, these treatments neither fully prevent the course of development of muscular disorder nor fully improve the function of dystrophic muscle. Thus, extensive reasearch work with some novel inhibitors of oxidative stress, SL Ca-entry systems such as store-operated Ca-channels, Na-Ca exchanger and Ca/Mg-ecto ATPase (Ca-gating mechanism), as well as SR Ca-release and Capump systems needs to be carried out in combination of gene therapy for improved beneficial effects in muscular dystrophy.