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Life Sci Alliance. 2020 Feb 4;3(3). pii: e202000646. doi: 10.26508/lsa.202000660. Print 2020 Mar.

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration.

Author information

1
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
2
Department Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
3
Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
4
Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy.
5
Department of Biology, University of Rome Tor Vergata, Rome, Italy castagnoli@uniroma2.it.
6
Department of Biology, University of Rome Tor Vergata, Rome, Italy cesareni@uniroma2.it.
7
Department of Biology, University of Rome Tor Vergata, Rome, Italy francesca.sacco@uniroma2.it.

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.

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