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.
Highlights
The interaction between the dystrophin protein and the dystrophinassociated protein complex (DAPC), which spans the sarcolemmal membrane, is essential for the integrity of the muscle fibers (Petrof et al, 1993)
As lipid-rich diets have a positive effect on the Duchenne muscular dystrophy (DMD) phenotype, we investigated the effects of in vivo metabolic reprogramming on dystrophic fibro/ adipogenic progenitors (FAPs) and muscle satellite cells (MuSCs) biology
We found that most of the key enzymes involved in fatty acid metabolism, tricarboxylic acid cycle (TCA) cycle, and oxidative phosphorylation (OxPhos) are significantly down-regulated in dystrophic as compared with wild-type FAPs (Fig 1A and B)
Summary
The interaction between the dystrophin protein and the dystrophinassociated protein complex (DAPC), which spans the sarcolemmal membrane, is essential for the integrity of the muscle fibers (Petrof et al, 1993). Dystrophin deficiency and the ensuing decrease of the DAPC components in Duchenne muscular dystrophy (DMD) patients (Emery, 1998) dramatically increases myofiber fragility upon muscle contraction and affects calcium and sodium homeostasis (Ohlendieck & Campbell, 1991; Petrof et al, 1993). Mitochondrial enzymes of the tricarboxylic acid cycle (TCA) (Lindsay et al, 2018) and of the electron transport chain (Rybalka et al, 2014) are significantly decreased. These functional defects correlate with mitochondrial structural abnormalities. Dense and dilated mitochondria with altered cristae as well as swollen mitochondria have been described in muscle fibers of DMD patients (Rybalka et al, 2014)
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