Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetes patients

Aging and type 2 diabetes mellitus (T2DM) are associated with impaired skeletal muscle function and degeneration of the skeletal muscle microenvironment. However, the origin and mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscles...

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Published inbioRxiv
Main Authors Farup, Jean, Just, Jesper, De Paoli, Frank, Lin, Lin, Jonas Brorson Jensen, Billeskov, Tine, Ines Sanchez Roman, Comert, Cagla, Andreas Buch Moeller, Madaro, Luca, Groppa, Elena, Rikard, Goran Fred, Kampmann, Ulla, Pedersen, Steen B, Bross, Peter, Stevnsner, Tinna, Eldrup, Nikolaj, Pers, Tune H, Rossi, Fabio Mv, Pier Lorenzo Puri, Jessen, Niels
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 25.08.2020
Subjects
Adipogenesis
Aging
CD90 antigen
Collagen
Degeneration
Diabetes
Diabetes mellitus (non-insulin dependent)
Extracellular matrix
Fermentation
Glycolysis
Lactic acid
Metformin
Musculoskeletal system
Phenotypes
Platelet-derived growth factor
Skeletal muscle
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Summary:Aging and type 2 diabetes mellitus (T2DM) are associated with impaired skeletal muscle function and degeneration of the skeletal muscle microenvironment. However, the origin and mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscles of T2DM patients exibit pathologcial degenerative remodeling of the extracellular matrix that was associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90) - the FAPCD90+. We identified Platelet-derived growth factor (PDGF) signaling as key regulator of human FAP biology, as it promotes proliferation and collagen production at the expense of adipogenesis, an effect accompanied with a metabolic shift towards glycolytic lactate fermentation. FAPsCD90+ showed a PDGF-mimetic phenotype, with high proliferative activity and clonigenicity, increased production of extracellular matrix production and enhanced glycolysis. Importantly, the pathogenic phenotype of T2DM FAPCD90+ was reduced by treatment with the anti-diabet drug Metformin. These data identiy PDGF-driven conversion of a sub-population of FAPs as a key event in the pathogenic accumulation of extracellular matrix in T2DM muscles. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.08.25.243907