Role of macrophages in degenerative myopathies and fibrosis.

Inflammatory cells control stem cell fate/behaviour coordinating tissue repair by adopting sequential inflammatory profiles.

This tightly regulated balance is skewed in patients with late phases of chronic diseases, like muscle dystrophies (Serrano and Munoz-Canoves, 2017).

In degenerative myopathies, unlike in the regenerating muscle, macrophage subsets show mixed phenotypes that exhibit different functions, mixing at the same place subsets that are beneficial for myogenesis and other subsets that are detrimental promoting fibrosis (Chazaud, 2020; Juban et al., 2018; McArthur et al., 2020). However, surface markers allowing to target precisely those subsets, as well as the major signaling pathways controling their behavior, are lacking.

ESR3 will investigate this peculiar phenotype by performing single cell RNAseq to identify the precise molecular signature of macrophage subsets in diseased muscle.

Selected identified gene of interest will be deleted through floxed strains with specific macrophage-CRE including LysM, or through electroporation of shRNA to identify their roles in fibrosis and myogenesis. Complementary, in vitro LOF/GOF experiments in co-cultures of fibroblasts and myoblasts will be performed to validate the role of these macrophage-regulatory pathways on the regulation of of matrix remodelling versus fibrosis.

Chazaud, B. (2020). Inflammation and Skeletal Muscle Regeneration: Leave It to the Macrophages! Trends Immunol.
Juban, G., Saclier, M., Yacoub-Youssef, H., Kernou, A., Arnold, L., Boisson, C., Ben Larbi, S., Magnan, M., Cuvellier, S., Theret, M., et al. (2018). AMPK Activation Regulates LTBP4-Dependent TGF-beta1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy. Cell Rep 25, 2163-2176 e2166.
McArthur, S., Juban, G., Gobbetti, T., Desgeorges, T., Theret, M., Gondin, J., Toller-Kawahisa, J.E., Reutelingsperger, C.P., Chazaud, B., Perretti, M., et al. (2020). Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation. J Clin Invest 130, 1156-1167.
Serrano, A.L., and Munoz-Canoves, P. (2017). Fibrosis development in early-onset muscular dystrophies: Mechanisms and translational implications. Semin Cell Dev Biol 64, 181-190.