FGF-2-dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

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
AAV-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 years versus < 55 years 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 novel
pathway to combat fat accumulation in aged human skeletal muscle.