TY - JOUR
T1 - Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration
AU - Reggio, Alessio
AU - Rosina, Marco
AU - Krahmer, Natalie
AU - Palma, Alessandro
AU - Petrilli, Lucia Lisa
AU - Maiolatesi, Giuliano
AU - Massacci, Giorgia
AU - Salvatori, Illari
AU - Valle, Cristiana
AU - Testa, Stefano
AU - Gargioli, Cesare
AU - Fuoco, Claudia
AU - Castagnoli, Luisa
AU - Cesareni, Gianni
AU - Sacco, Francesca
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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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U2 - 10.26508/lsa.202000660
DO - 10.26508/lsa.202000660
M3 - Article
C2 - 32019766
AN - SCOPUS:85079003594
VL - 3
JO - Life Science Alliance
JF - Life Science Alliance
SN - 2575-1077
IS - 3
ER -