Necroptosis mediates myofibre death in dystrophin-deficient mice

Jennifer E. Morgan (), Alexandre Prola, Virginie Mariot, Veronica Pini, Jinhong Meng, Christophe Hourde, Julie Dumonceaux, Francesco Conti, Frederic Relaix, Francois-Jerôme Authier, Laurent Tiret, Francesco Muntoni and Maximilien Bencze ()
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Jennifer E. Morgan: UCL Great Ormond Street Institute of Child Health
Alexandre Prola: EFS
Virginie Mariot: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust
Veronica Pini: UCL Great Ormond Street Institute of Child Health
Jinhong Meng: UCL Great Ormond Street Institute of Child Health
Christophe Hourde: Université Savoie Mont Blanc
Julie Dumonceaux: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust
Francesco Conti: UCL Great Ormond Street Institute of Child Health
Frederic Relaix: EFS
Francois-Jerôme Authier: EFS
Laurent Tiret: EFS
Francesco Muntoni: UCL Great Ormond Street Institute of Child Health
Maximilien Bencze: UCL Great Ormond Street Institute of Child Health

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Duchenne muscular dystrophy (DMD) is a severe degenerative disorder caused by mutations in the dystrophin gene. Dystrophin-deficient muscles are characterised by progressive myofibre necrosis in which inflammation plays a deleterious role. However, the molecular mechanisms underlying inflammation-induced necrosis in muscle cells are unknown. Here we show that necroptosis is a mechanism underlying myofibre death in dystrophin-deficient muscle. RIPK1, RIPK3 and MLKL are upregulated in dystrophic mouse myofibres. In human DMD samples, there is strong immunoreactivity to RIPK3 and phospho-MLKL in myofibres. In vitro, TNFα can elicit necroptosis in C2C12 myoblasts, and RIPK3 overexpression sensitises myoblasts to undergo TNF-induced death. Furthermore, genetic ablation of Ripk3 in mdx mice reduces myofibre degeneration, inflammatory infiltrate, and muscle fibrosis, and eventually improves muscle function. These findings provide the first evidence of necroptotic cell death in a disease affecting skeletal muscle and identify RIPK3 as a key player in the degenerative process in dystrophin-deficient muscles.

Date: 2018
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DOI: 10.1038/s41467-018-06057-9

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