The growth factor FGF21 maintains neuromuscular junction through histone deacetylase HDAC4 in denervation-induced skeletal muscle atrophy

Skeletal muscles undergo atrophy in response to denervation and neuromuscular disease. Understanding the mechanisms by which denervation drives muscle atrophy is crucial for developing therapies against neurogenic muscle atrophy. Here, we identified muscle-secreted fibroblast growth factor 21 (FGF21) as a key inducer of atrophy following muscle denervation. In denervated skeletal muscles, Fgf21 is the most robustly upregulated member of the Fgf family and acts in an autocrine/paracrine manner to promote muscle atrophy. Silencing Fgf21 in muscle prevents denervation-induced muscle wasting by preserving neuromuscular junction (NMJ) innervation. Conversely, forced expression of FGF21 in muscle reduces NMJ innervation, leading to muscle atrophy. Mechanistically, TGFB1 released by denervated fibro-adipogenic progenitors (FAPs) upregulates Fgf21 expression through the JNK/c-Jun axis. The resulting increase in FGF21 protein reduces the cytoplasmic level of histone deacetylase 4 (HDAC4), culminating in muscle atrophy. HDAC4 knockdown abolishes the atrophy-resistant effects observed in Fgf21-deficient denervated muscles, resulting in muscle atrophy. Our findings reveal a novel role and heretofore unrecognized mechanism of FGF21 in skeletal muscle atrophy, suggesting that inhibiting muscular FGF21 could be a promising strategy for mitigating skeletal muscle atrophy.