Metabolic Reprogramming of Fibro/Adipogenic Progenitors Facilitates Muscle Regeneration

Abstract

SummaryDystrophin deficiency causes chronic wasting of the skeletal muscle tissue leading to patient respiratory or heart failure and, finally, death. In addition to fiber fragility, the absence of the dystrophin protein, as in Duchenne Muscular Dystrophy (DMD), causes a variety of poorly understood secondary effects. Notably muscle fibers of dystrophic individuals are characterized by mitochondrial dysfunctions, as revealed by a reduced ATP production rate and by defective oxidative phosphorylation (OxPhos). Here we show that in a mouse model of DMD (mdx), the interstitial Fibro/Adipogenic Progenitor (FAP) cells are also characterized by a dysfunctional mitochondrial metabolism which correlates with an increased adipogenic differentiation potential. Using high-sensitivity mass spectrometry-based proteomics, we report that a short-term high-fat diet regimen reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we discovered a high-fat dependent modulation of the crucial hub protein, β-catenin, which controls follistatin expression. Our results reveal that a short-term high-fat diet restores the key role of FAPs in enhancing the myogenic activity of the skeletal muscle stem cells in dystrophic mice. Consistently, we observe that muscle regeneration in the mdx mouse is significantly improved by the short-term high-fat diet. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of Duchenne Muscular Dystrophy.

Keywords: Skeletal Muscle Regeneration, metabolic reprogramming, High-fat Diet, Fibro/Adipogenic Progenitors, Muscle Satellite Cells, Proteomics, Stem Cell Metabolism, Duchenne Muscular Dystrophy, β-Catenin.