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Updated: Jul 9, 2025
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy
Erica Mina1, Elisabeth Wyart1, Roberta Sartori2
1Department 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.
Insights
Cancer cachexia causes muscle wasting by disrupting Bone Morphogenetic Protein (BMP) signaling. Targeting erythroferrone (ERFE) and FKBP12 with FK506 restores BMP signaling, preventing muscle loss and offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Skeletal muscle atrophy is a significant complication of cachexia, a wasting syndrome associated with chronic diseases, representing a major unmet medical need.
- Alterations in Bone Morphogenetic Protein (BMP)-Smad1/5/8 signaling pathways are increasingly recognized as key contributors to muscle catabolism in cachexia.
- Understanding these signaling perturbations is crucial for developing effective therapeutic interventions.
Purpose of the Study:
- To identify key regulators of BMP resistance in cancer-induced cachexia.
- To investigate the therapeutic potential of targeting the identified regulators to counteract muscle wasting.
Main Methods:
- Analysis of muscle biopsies from cachectic cancer patients and murine cachexia models.
- Investigated the role of erythroferrone (ERFE) and FKBP12 in promoting BMP resistance.
- Utilized gene knockdown (Erfe, Fkbp12) and pharmacological inhibition (FK506) in cachectic mice models.
- Assessed muscle mass, body weight, protein synthesis, and neuromuscular junction integrity.
Main Results:
- Erythroferrone (ERFE) and FKBP12 were identified as major contributors to BMP resistance in cancer cachexia.
- ERFE expression in muscle is upregulated in cachectic patients and mice, driven by STAT3.
- Knockdown of Erfe or Fkbp12 ameliorated muscle wasting in cachectic mice.
- Low-dose FK506 treatment restored BMP-Smad1/5/8 signaling, rescued myotube atrophy via protein synthesis induction, and prevented muscle/body weight loss in tumor-bearing mice.
Conclusions:
- The ERFE-FKBP12 axis plays a critical role in mediating BMP resistance and muscle wasting in cancer cachexia.
- Targeting FKBP12 with FK506 effectively bypasses ERFE-mediated BMP resistance, restoring signaling and preventing muscle atrophy.
- This study suggests that targeting the ERFE-FKBP12 axis holds significant therapeutic potential for treating muscle wasting in cachexia.
