Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia

  • Nat Metab. 2025 Nov 12. doi: 10.1038/s42255-025-01397-5.
Elia Angelino  #  1  2 ,  Lorenza Bodo  #  3 ,  Roberta Sartori  4  5 ,  Valeria Malacarne  3  6 ,  Beatrice D'Anna  3 ,  Nicolò Formaggio  7 ,  Suvham Barua  3  6 ,  Tommaso Raiteri  6 ,  Andrea Lauria  8  9 ,  Simone Reano  10 ,  Alessandra Murabito  3 ,  Monica Nicolau  3  11 ,  Fabiana Ferrero  3  12 ,  Camilla Pezzini  4  5 ,  Giulia Rossino  3  6 ,  Francesco Favero  6  10 ,  Michele Valmasoni  13 ,  Nicoletta Filigheddu  6 ,  Alessio Menga  10  14 ,  Davide Corà  6  10 ,  Emilio Hirsch  3 ,  Salvatore Oliviero  8  9  15 ,  Vittorio Sartorelli  16 ,  Valentina Proserpio  8  9 ,  Alessandra Ghigo  3 ,  Marco Sandri  4  5 ,  Paolo E Porporato  3 ,  Daniela Talarico  17 ,  Giuseppina Caretti  18 ,  Andrea Graziani  19  20
Affiliations
  • 1. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, Italy. [email protected].
  • 2. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy. [email protected].
  • 3. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, Italy.
  • 4. Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • 5. Veneto Institute of Molecular Medicine, Padova, Italy.
  • 6. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
  • 7. Institute of Oncology Research, Università della Svizzera italiana, Lugano, Switzerland.
  • 8. Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.
  • 9. Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, Italy.
  • 10. Center on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.
  • 11. Center for Cardiovascular and Muscular Diseases, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 12. Department of Experimental Medicine, University of Genoa, Genoa, Italy.
  • 13. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
  • 14. Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
  • 15. Italian Institute for Genomic Medicine, Candiolo, Italy.
  • 16. Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, MD, USA.
  • 17. IRCCS Ospedale San Raffaele, Comprehensive Cancer Center, Milan, Italy.
  • 18. Department of Biosciences, University of Milano, Milan, Italy.
  • 19. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, Italy. [email protected].
  • 20. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy. [email protected].
  • # Contributed equally.
PMID: 41224958 DOI: 10.1038/s42255-025-01397-5
Abstract

Skeletal muscle wasting is a defining feature of Cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in Cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that Cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP-PKA-CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP-PKA-CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during Cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in Cancer cachexia.

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