Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

Abstract

In Duchenne muscular dystrophy (DMD), the absence of the dystrophin protein 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. Here, we show that in a mouse model of DMD (mdx), fibro/adipogenic progenitors (FAPs) are characterized by a dysfunctional mitochondrial metabolism which correlates with increased adipogenic potential. Using high-sensitivity mass spectrometry–based proteomics, we report that a short-term high-fat diet (HFD) reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we revealed that HFD modulates the β-catenin–follistatin axis. These changes are accompanied by significant amelioration of the histological phenotype in dystrophic mice. Transplantation of purified FAPs from HFD-fed mice into the muscles of dystrophic recipients demonstrates that modulation of FAP metabolism can be functional to ameliorate the dystrophic phenotype. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of DMD.

Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors

“…Further, HDAC inhibitors blocked adipogenic differentiation of FAPs and improved their ability to promote differentiation of MuSCs, through upregulation of the soluble factor follistatin in early stage, but not late stage, mdx mice; which are also characterized by metabolic defects (Mozzetta et al, 2013). Using the same mdx mouse model of muscular dystrophy, Reggio et al (2019) demonstrated that follistatin is diminished in FAPs due to reduced β-catenin signaling. However, short-term high fat diet feeding reversed this defect by increasing β-catenin levels which promoted IGF-1 and follistatin expression and release leading to improved ability of FAPs to support myogenesis and muscle regeneration (Reggio et al, 2019).…”

“…In contrast, fibrogenesis and chondrogenesis seems to require utilization of glycolysis during differentiation (Shyh-Chang et al, 2013;Zhao et al, 2019). FAPs from regenerating mdx muscle have an increase in glycolytic proteins and a reduction of mitochondrial proteins compared to control mice (Marinkovic et al, 2019) resulting in mdx FAPs favoring glycolysis over oxidative metabolism (Reggio et al, 2019). Interestingly, these metabolic changes were associated with greater proliferative capacity and adipogenic potential in vitro which was reversed by inhibiting glycolysis and forcing oxidative metabolism (Reggio et al, 2019).…”

“…FAPs from regenerating mdx muscle have an increase in glycolytic proteins and a reduction of mitochondrial proteins compared to control mice (Marinkovic et al, 2019) resulting in mdx FAPs favoring glycolysis over oxidative metabolism (Reggio et al, 2019). Interestingly, these metabolic changes were associated with greater proliferative capacity and adipogenic potential in vitro which was reversed by inhibiting glycolysis and forcing oxidative metabolism (Reggio et al, 2019). This impaired metabolic phenotype was reversed in vivo by providing a short-term high fat diet which stimulated oxidative metabolism in FAPs (Reggio et al, 2019).…”

“…Interestingly, these metabolic changes were associated with greater proliferative capacity and adipogenic potential in vitro which was reversed by inhibiting glycolysis and forcing oxidative metabolism (Reggio et al, 2019). This impaired metabolic phenotype was reversed in vivo by providing a short-term high fat diet which stimulated oxidative metabolism in FAPs (Reggio et al, 2019). Conversely, long-term high fat diet, and obesity are associated with increased muscle adiposity and fibrosis (Goodpaster et al, 2000).…”

“…Interestingly, despite the importance of paracrine factor signaling on FAP function, relatively little attention has been paid to the role of metabolic stress on the FAP secretome. One myogenic paracrine factor that has received some attention in the literature is follistatin (Mozzetta et al, 2013;Reggio et al, 2019). Follistatin is a myostatin inhibitor, and thus promotes muscle growth (Lee and McPherron, 2001) and glucose uptake (Han et al, 2019).…”