Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition associated with chronic diseases, which remains an unmet medical need.
Alterations in bone morphogenetic protein (BMP)–Smad1/5/8 signaling are emerging as key drivers of muscle catabolism; therefore, characterizing these disruptions is essential for developing therapeutic strategies.
We identified two promoters of “BMP resistance” in cancer cachexia — the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in muscle biopsies from cachectic cancer patients and in murine models of cachexia, where its expression is driven by STAT3. Moreover, knockdown of Erfe or Fkbp12 mitigates muscle wasting in cachectic mice.
To overcome ERFE-mediated BMP resistance and release the signaling brake, we targeted FKBP12 with a low dose of FK506. FK506 restored BMP–Smad1/5/8 signaling and counteracted myotube atrophy by inducing protein synthesis. In tumor-bearing cachectic mice, FK506 prevented body and muscle weight loss and preserved neuromuscular junction integrity, suggesting a therapeutic potential for targeting the ERFE–FKBP12 axis.
