FK506 BYPASSES THE EFFECT OF ERYTHROFERRONE IN CANCER CACHEXIA SKELETAL MUSCLE ATROPHY

Erica MINA¹, Paolo PORPORATO¹, Elisabeth WYART¹, Roberta SARTORI², Elia ANGELINO¹, Ivan ZAGGIA¹, Graziani ANDREA¹, Marco SANDRI², Kautz LÉON³, Laura SILVESTRI⁴

¹Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, Turin, Italy
²Department of Biomedical Sciences, University of Padova, Padova, Italy
³IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS), Toulouse, France
⁴Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy

Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need.

BMP-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutical approaches.

We identified two promoters of BMP-resistance in cancer cachexia, specifically the BMP-scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies, and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock-down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP-resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutical potential for targeting the ERFE-FKBP12 axis.