Necroptosis, a programmed form of necrosis, participates in muscle degeneration in Duchenne muscular dystrophy
Neuromuscular Disorders(2017)
Abstract
Efforts to treat Duchenne muscular dystrophy (DMD) mainly focus on strategies aimed at increasing dystrophin expression, or enhancing muscle regeneration/growth. However, the process of cell death in muscle wasting disorders has been largely overlooked. In DMD, fibres die with a necrotic morphology, making myonecrosis a central process in its pathogenesis. Inflammation and oxidative stress play a significant part in muscle loss, but how inflammation induces myonecrosis is still unknown. Lately, there has been a conceptual revolution in the cell death field, with the discovery of regulated forms of necrosis. In particular, necroptosis, a RIPK3-dependent programmed cell death, plays a major role in cell death following inflammation-induced injuries in several tissues and is commonly initiated by ligands to the TNF Receptor superfamily members. As a programmed cell death mode, necroptosis can be pharmacologically prevented. Its involvement in skeletal muscle degeneration has not yet been reported. We are currently investigating the involvement of necroptosis in inflammatory-induced myonecrosis, and more specifically in the pathogenesis of DMD. In vitro, we found that TNFα can trigger necroptosis in C2C12 cell line, suggesting that muscle cells can undergo necroptosis upon inflammatory challenge. In vivo, we found evidence of necroptosis in human and mouse dystrophin-deficient muscles. By depleting RIPK3 in mdx mice, we significantly decreased myonecrosis. Together, our data demonstrate that the necroptotic machinery is involved in DMD pathogenesis and that its prevention could represent a new therapeutic target.
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Key words
Skeletal muscle,Duchenne muscular dystrophy,Inflammation,Necrosis,Necroptosis
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