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

Farup, J.; Just, J.; de Paoli, F.; Lin, L.; Jensen, J. B.; Billeskov, T.; Roman, I. S.; Comert, C.; Moeller, A. B.; Madaro, L.; Groppa, E.; Fred, R. G.; Kampmann, U.; Pedersen, S. B.; Bross, P.; Stevnsner, T.; Eldrup, N.; Pers, T. H.; Rossi, F. M. V.; Puri, P. L.; Jessen, N.

doi:10.1101/2020.08.25.243907

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bioRxiv · 10.1101/2020.08.25.243907

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

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Abstract

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 exhibit pathological 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 clonogenicity, increased production of extracellular matrix production and enhanced glycolysis. Importantly, the pathogenic phenotype of T2DM FAPCD90+ was reduced by treatment with the anti-diabetic drug Metformin. These data identify PDGF-driven conversion of a sub-population of FAPs as a key event in the pathogenic accumulation of extracellular matrix in T2DM muscles.

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Farup, J., Just, J., de Paoli, F., Lin, L., Jensen, J. B., Billeskov, T., Roman, I. S., Comert, C., Moeller, A. B., Madaro, L., Groppa, E., Fred, R. G., Kampmann, U., Pedersen, S. B., Bross, P., Stevnsner, T., Eldrup, N., Pers, T. H., Rossi, F. M. V., Puri, P. L., Jessen, N.. 2020-08-25. Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetes patients. https://doi.org/10.1101/2020.08.25.243907

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