FGF-2-Dependent Signaling Activated in Aged Human Skeletal Muscle Promotes Intramuscular Adipogenesis

Abstract Background: A unique feature of muscle during aging, obesity and type 2 diabetes is the appearance adipose tissue between skeletal fibers, intramuscular (IMAT). IMAT generally associated with systemic insulin resistance, decreased strength and, in older adults, impaired mobility. large body work over last years have addressed origin IMAT. Skeletal contains preadipocyte progenitors termed fibro/adipogenic (FAPs) that normally do not form adipocytes, but proliferate injury to support commitment myogenic progenitor cells repair. However, under conditions outlined above, FAPs differentiate adipocytes give rise The molecular cues trigger this pathogenesis are unknown strategies can modulate fate their propensity disease states urgently needed. Methods: We used cloning genome editing techniques together a variety biochemical, molecular, genomic, transcriptomic proteomic analyses pre-adipocyte cell lines, primary isolated from human mouse muscle, biopsies, animal models. Results: Using multiple screening assays upstream downstream master regulator myogenesis, microRNA (miR)-29a, we located secreted protein adipogenic inhibitor SPARC an FGF-2 signaling pathway conserved mice humans activated aged humans. identified as increases miR-29a promoter activity gene expression via MEK1/2/MAPK consequently decreases target SPARC. induces miR-29a/SPARC axis through transcriptional activation FRA-1, which binds activates evolutionary AP-1 site element proximal promoter. CRISPR/Cas9-mediated genomic deletions recognition elements Sparc 3?UTR AAV-mediated overexpression or revealed regulates differentiation vitro formation vivo. donors > 75 versus < 55 showed FGF-2-dependent increased Conclusion: only stimulates growth, also promotes adipogenesis targeting FAPs. Thus, our data highlights disparate role adult reveals novel pathway, has potential provide innovative diagnostic therapeutic approaches combat fat accumulation muscle.