Mechanisms of Myofibre Death in Muscular Dystrophies: The Emergence of the Regulated Forms of Necrosis in Myology

Abstract

Myofibre necrosis is a central pathogenic process in muscular dystrophies (MD). As post-lesional regeneration cannot fully compensate for chronic myofibre loss, interstitial tissue accumulates and impairs muscle function. Muscle regeneration has been extensively studied over the last decades, however, the pathway(s) controlling muscle necrosis remains largely unknown. The recent discovery of several regulated cell death (RCD) pathways with necrotic morphology challenged the dogma of necrosis as an uncontrolled process, opening interesting perspectives for many degenerative disorders. In this review, we focus on how cell death affects myofibres in MDs, integrating the latest research in the cell death field, with specific emphasis on Duchenne muscular dystrophy, the best-known and most common hereditary MD. The role of regulated forms of necrosis in myology is still in its infancy but there is increasing evidence that necroptosis, a genetically programmed form of necrosis, is involved in muscle degenerating disorders. The existence of apoptosis in myofibre demise will be questioned, while other forms of non-apoptotic RCDs may also have a role in myonecrosis, illustrating the complexity and possibly the heterogeneity of the cell death pathways in muscle degenerating conditions.

Keywords

• muscular dystrophies
• duchenne muscular dystrophy
• myonecrosis
• myofibre
• regulated cell death
• regulated necrosis