FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy
2023
Mina, Erica | Wyart, Elisabeth | Sartori, Roberta | Angelino, Elia | Zaggia, Ivan | Rausch, Valentina | Maldotti, Mara | Pagani, Alessia | Hsu, Myriam | Friziero, Alberto | Sperti, Cosimo | Menga, Alessio | Graziani, Andrea | Hirsch, Emilio | Oliviero, Salvatore | Sandri, Marco | Conti, Laura | Kautz, Léon | Silvestri, Laura | Porporato, Paolo | Università degli studi di Torino = University of Turin (UNITO) | Università degli Studi di Padova = University of Padua (Unipd) | Veneto Institute of Molecular Medicine [Padova, Italy] (VIMM) | Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO) | Italian Institute for Genomic Medicine (IIGM) | IRCCS Ospedale San Raffaele [Milan, Italy] | Kyoto University | Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP) | Institut de Recherche en Santé Digestive (IRSD) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR) | The research leading to these results has received funding from AIRC under MFAG 2018 - ID. 21564 project - P.I. Porporato Paolo Ettore; PoC Instrument 2021; PoC ToInProVE2; Consorzio Interuniversitario per le Biotecnologie (CIB); and AIRC under MFAG 2022 ID. 25908 project - P.I. Leon Kautz and Project Age-it, PE0000015, PNRR MUR - M4C2 1.3 funded by Next -Generation EU to P.I. Andrea Graziani. V.R. fellowship was funded by AIRC. | European Project: 715491,H2020
International audience
Mostrar más [+] Menos [-]Inglés. Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic 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 therapeutic potential for targeting the ERFE-FKBP12 axis.
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