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标题：FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis
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作者：Sebastian Mathes ; Alexandra Fahrner ; Umesh Ghoshdastider 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2021013118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance A unique feature of muscle during aging, obesity, and type 2 diabetes is the appearance of adipose tissue between skeletal muscle fibers, the intramuscular adipose tissue (IMAT). IMAT is generally associated with insulin resistance, decreased muscle strength, and, in older adults, impaired mobility. However, the molecular cues that cause the pathological formation of IMAT are currently unknown. This work uncovers a conserved FGF-2–mediated signaling axis that up-regulates the expression of microRNA-29a, triggering a decrease of the adipogenic inhibitor SPARC and increased fat formation in aged skeletal muscle. We show that FGF-2–dependent signaling modulates the fate of fibro/adipogenic progenitors and their propensity to differentiate to intramuscular adipocytes, which reveal therapeutic opportunities to prevent IMAT formation in human skeletal muscle. Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle.
关键词：enskeletal muscle;FGF-2;SPARC;FRA-1;IMAT