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

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit 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 FAP(CD90+). We identified Platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPs(CD90+) showed a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity and production of extracellular matrix. FAP(CD90+) proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a sub-population of FAPs as a key event in the fibrosis development in T2DM muscle

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

Funding was provided by the A.P. Møller Foundation; Riisfort Foundation; Toyota Foundation; Independent Research Fund Denmark (DFF–5053-00195 to J.F.); Steno Diabetes Center Aarhus, which is partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF17OC0027242 to N.J. and NNF16OC0021496 to T.H.P.); Lundbeck Foundation (R190-2014-3904 to T.H.P.); Roche per la Ricerca 2019 to L.M.; and NIH/NIAMS (R01AR076247-01 to P.L.P.).Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)—the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu