Role of Apoptosis in Myopathies

Muscle fiber atrophy and loss is a characteristic of a wide range of neuromuscular affections. Over the past years, there has been increasing evidence that apoptotic cell death mechanisms contribute to this loss. While the initiating stimuli of apoptotic muscle fiber death such as homeostatic dysregulations and oxidative stress seems to be manifold and assumedly disease-specific the up-regulation of the mitochondria-associated factors bax and bcl-2 as well as caspases such as caspase-9 and -3 indicate that predominant effectors involve permeability transition pores in the mitochondrial membrane and subsequent caspase activations which_ confer the typical morphological and biochemical features of apoptosis such as TUNEL-positive DNA-fragmentation and formation of apoptotic bodies. Deeper insights in muscle fiber apoptosis revealed that apoptosis of multinucleated muscle fibers with individual nuclei controlling successive muscle fiber segments is different from that seen in mononucleated cells. It is likely that apoptotic degradation of nuclei and contractile elements is a localized event in muscle fiber segments leading to muscle fiber atrophy and finally loss in various diseases. In the absence of effective primary treatments, there is hope that interventions in muscle fiber apoptosis will bear promising therapeutic strategies, especially in slowly progressive diseases such as muscular dystrophies and denervating disorders.