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Publications

Journal Article Research Support, Non-U.S. Gov't Ppublish 4 citations

PubMed: 38052214 DOI: 10.1016/j.xcrm.2023.101306

FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy.

Cell Rep Med 4(12):101306

Authors: Erica Mina, Elisabeth Wyart, Roberta Sartori, Elia Angelino, Ivan Zaggia, Valentina Rausch, Mara Maldotti, Alessia Pagani, Myriam Y Hsu, Alberto Friziero, Cosimo Sperti, Alessio Menga, Andrea Graziani, Emilio Hirsch, Salvatore Oliviero, Marco Sandri, Laura Conti, Léon Kautz, Laura Silvestri, Paolo E Porporato

Affiliations

  • Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, 10126 Torino, Italy.
  • Department of Biomedical Sciences, University of Padova, Padova, Italy; VIMM: Veneto Institute of Molecular Medicine, Padova, Italy.
  • Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, 10126 Torino, Italy; Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy.
  • Department of Life Sciences and Systems Biology, Molecular Biotechnology Center "Guido Tarone", University of Torino, 10126 Torino, Italy; Italian Institute for Genomic Medicine (IIGM), Sp142 Km 3.95, 10060 Candiolo, Torino, Italy.
  • Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, 10126 Torino, Italy; Division of Cell Fate Dynamics and Therapeutics, Department of Biosystems Science, Institute for Life and Medical Sciences (LiMe), Kyoto University, Kyoto, Japan.
  • Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; General Surgery 1, Padova University Hospital, Padova, Italy.
  • General Surgery 2, Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy.
  • IRSD, Université de Toulouse, INSERM, INRAE, ENVT, University Toulouse III - Paul Sabatier (UPS), Toulouse, France.
  • Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy.
  • Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, 10126 Torino, Italy.

Abstract

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.

MeSH

Muscular Atrophy, Muscles, Biological Science Disciplines, Neoplasms, Tacrolimus, Therapeutics, Muscle, Skeletal, Cancer-Associated Cachexia

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