2. Academic Validation
  3. Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia

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

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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