In Duchenne muscular dystrophy (DMD), myofibres die with a necrotic morphology, however the cell death mechanisms are largely unknown. Inflammation plays a significant part in muscle degeneration.

Necroptosis is a newly identified programmed form of necrosis, which is driven by receptor interacting protein kinase 3 (RIPK3). It plays a major role in the inflammation-induced injuries in several tissues.

We are currently investigating the involvement of necroptosis in DMD pathogenesis.

In vitro, muscle cells were challenged with inflammatory stimuli, with or without various protein inhibitors. Cell toxicity was monitored by the quantification of ATP content (reflecting cell survival) and protease realease (reflecting membrane permeability)

In vivo, dystrophic skeletal muscles from mdx mice (a mouse model for DMD) were analyzed. Mdx mice were crossed with RIPK3 KO mice.

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.

Our data suggest that the necroptosis machinery is involved in the cell death affecting myofibres in DMD pathogenesis.