Cysteinet Dysregulation in Muscular Dystrophies: A Pathogenic Network Susceptible to Therapy.

Abstract

Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group. Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies. The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.