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: apoptosis; duchenne muscular dystrophy; muscular dystrophies; myofibre; myonecrosis; necroptosis; regulated cell death; regulated necrosis.

Figure 1

General view of the main cell death modalities with relevance in myology. Cell death can result from an accidental/unregulated or cell-regulated process. Accidental cell death (ACD) refers to a cell demise for which no identified signalling pathway is involved in cell death execution. Regulated cell death (RCD) refers to a cell death for which activation and execution are controlled, positively or negatively by a biochemical process. Cell demise can be genetically and/or pharmacologically prevented. RCDs pathways can lead to apoptotic or necrotic morphologies depending on the nature of the executioner machinery. Apoptosis: RCD which is controlled by non-inflammatory caspase proteases, culminating in a cell demise associated with typical morphology of cell rounding, nuclear condensation; membrane blebbing and apoptotic body formation. No early plasma membrane permeabilization is assessed. Two subtypes of apoptotic pathways are identified: intrinsic and extrinsic apoptosis, respectively mediated by the apoptosome formation and Caspase 8 activation. Necrosis refers to cell death morphology associated with early plasma membrane permeabilization. Necrotic death can be the consequence of an ACD or a non-apoptotic RCD. Necroptosis is a subtype of necrotic RCD. Necroptosis is genetically controlled by the RIPK1-RIPK3-MLKL axis. Pyroptosis refers to another subtype of necrotic RCD. Pyroptosis is controlled by non-apoptotic caspase and GSDMD pores formation. CypD-dependent necrosis refers to an RCD which is mediated by the formation of a mitochondrial permeability transfer pore (mPT), culminating in a necrotic demise. A typical consequence of necrotic morphology over apoptosis is the release of DAMPs, the infiltration and activation of myeloid infiltrate and the promotion of a cytotoxic environment including pro-inflammatory cytokines.

Figure 2

Model for necroptosis involvement in Duchenne muscular dystrophy. Limb muscles from DMD boys are affected by chronic necrosis affecting myofibres. Genuine milestone of cell death events is likely to come from exercised-induced breaks into sarcolemma missing dystrophin (necrosis by accidental process affecting Myofibre 1, pink colour). A direct consequence of this accidental necrosis is the activation of necroinflammation via the release of DAMPs, and the classical activation of infiltrated macrophages. M1 macrophages secrete pro-inflammatory molecules, including death ligands such as TNFα binding to their DR. TNFα binding to TNFR1 of myofibres and recruits RIPK1. The kinase activity of RIPK1 is required to recruit RIPK3 into the necrosome complex. RIPK3-dependent phosphorylation of MLKL promotes the recruitment of p-MLKL to the sarcolemma, the formation of pores, and compromises the integrity of the plasma membrane of myofibres (necrosis by necroptotic pathway). Myofibre necroptosis is associated with tenascine C (TnC) release, which supports MuSC proliferation and early myogenesis.