Dystrophin Deficiency Causes Hyper‐Secretion and Atrophy in Myotubes

Abstract

The generally accepted view of the pathology of Duchenne muscular dystrophy is that absence of dystrophin renders myofibres abnormally susceptible to work-induced trauma, precipitating recurrent bouts of segmental myofibre necrosis. Necrosis stimulates inflammation and a regenerative response by myoblasts; the latter gradually becoming ineffective due to exhaustion of cells and accumulation of connective tissue driven by chronic inflammation. However, while searching for biomarkers in tissue cultures of dystrophic mouse muscle, we found phenomena that cause us to revise this picture. Using stable isotope labeled amino acids (SILAC) combined with liquid chromatography tandem mass spectrometry, we found that undamaged dystrophic myotubes are hypersecretive, excessively effluxing 57 intracellular proteins by mechanisms that cannot be identified as cell death, or generalized increase in passive leakiness. In addition dystrophic myotubes were smaller than wild-type and contain less protein and RNA per nucleus. We hypothesize that lack of dystrophin, as well as predisposing the myofibre to necrosis during physiological stress, has more profound general effects on its metabolic balance and its relationship with the extracellular environment, these potentially contributing to progressive muscle pathology. We identify myosin light chain 1 as a biomarker for in vitro drug screening. Supported by DoD.