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

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 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.

Toward a Consensus View of Mammalian Adipocyte Stem and Progenitor Cell Heterogeneity

“…In addition and again similar to mouse, human ASCs showed full adipogenic potential only when stimulated by a combination of several adipogenic triggers, as opposed to insulin alone [24]. Interestingly, a mesenchymal stem population characterized by THY1 expression has been described as being responsible for adipogenic degeneration of the muscle in individuals with type 2 diabetes [47]. Whether this population transcriptomically resembles hASCs remains to be robustly proven.…”

Evolving Roles of Muscle-Resident Fibro-Adipogenic Progenitors in Health, Regeneration, Neuromuscular Disorders, and Aging

“…These include mouse models of Collagen VI- (Noguchi et al, 2017;Mohassel et al, 2018), human DMD (Uezumi et al, 2014) and mouse models of DMD (Box 1) (Uezumi et al, 2011;Mozzetta et al, 2013;Lemos et al, 2015;Contreras et al, 2016Contreras et al, , 2020Ieronimakis et al, 2016;Kopinke et al, 2017;Mázala et al, 2020;Reggio et al, 2020;Giuliani et al, 2021), Facioscapulohumeral dystrophy (FSHD) (Bosnakovski et al, 2017(Bosnakovski et al, , 2020, Limb-girdle muscular dystrophy (LGMD) (Hogarth et al, 2019), and ALS neuromuscular disease (Gonzalez et al, 2017;Madaro et al, 2018). Increased muscle fibrosis and FAP expansion also occur after single and repeated cycles of intramuscular BaCl 2 , notexin, cardiotoxin, or glycerol administrations (Uezumi et al, 2010;Dadgar et al, 2014;Pessina et al, 2014;Contreras et al, 2016Contreras et al, , 2020Theret et al, 2021), vastus medialis muscles of compromised knee osteoarthritis patients (Ikemoto- Uezumi et al, 2017), human anterior cruciate ligament injuries (Fry et al, 2017), induced hindlimb ischemia (Santini et al, 2020), degenerated muscles of type 2 diabetic patients (Farup et al, 2020), obesity-mediated diaphragm dysfunction of chronic high-fat diet-fed mice (Buras et al, 2019), and surgical muscle traumas including denervation and laceration (Brandan et al, 1992;Pessina et al, 2014;Contreras et al, 2016;Madaro et al, 2018;Rebolledo et al, 2019). Muscle-resident FAP...…”

Signaling pathways regulating the fate of fibro/adipogenic progenitors (FAPs) in skeletal muscle regeneration and disease

“…In pathological conditions, FAP metabolism has been linked to their differentiation outcome. The glycolytic flux has been directly linked to their increased fibrogenic potential [183]. In DMD, mitochondrial alterations profoundly impact the metabolism of muscle fibers [184][185][186][187].…”