Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia
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.
Authors
- Leandro Bodo
- Giuseppina Caretti (ORCID: https://orcid.org/0000-0002-2322-6008)
- Valentina Proserpio (ORCID: https://orcid.org/0000-0003-2071-4206)
- Tommaso Raiteri (ORCID: https://orcid.org/0000-0002-3260-0647)
- Giulia Rossino
- Daniela Talarico (ORCID: https://orcid.org/0000-0001-5814-9244)
- Salvatore Oliviero (ORCID: https://orcid.org/0000-0002-3405-765X)
- Paolo E. Porporato (ORCID: https://orcid.org/0000-0001-8519-1552)
- Alessio Menga (ORCID: https://orcid.org/0000-0002-2827-5298)
- Alessandra Ghigo (ORCID: https://orcid.org/0000-0002-1193-5296)
- Andrea Lauria (ORCID: https://orcid.org/0000-0003-4753-861X)
- Francesco Favero (ORCID: https://orcid.org/0000-0003-3482-8335)
- Valeria Malacarne (ORCID: https://orcid.org/0000-0001-5893-8606)
- Alessandra Murabito (ORCID: https://orcid.org/0000-0003-3039-4285)
- Andrea Graziani (ORCID: https://orcid.org/0000-0002-6302-2317)
- Michele Valmasoni (ORCID: https://orcid.org/0000-0002-1462-8275)
- Barbara D’Anna (ORCID: https://orcid.org/0000-0001-8915-4097)
- Marco Sandri (ORCID: https://orcid.org/0000-0001-8509-7558)
- Shemanti Barua
- Davide Corà (ORCID: https://orcid.org/0000-0003-4123-1705)
- Vittorio Sartorelli (ORCID: https://orcid.org/0000-0002-9284-3675)
- Nicolò Formaggio
- Roberta Sartori (ORCID: https://orcid.org/0000-0002-2763-9838)
- Nicoletta Filigheddu (ORCID: https://orcid.org/0000-0002-3848-611X)
- Simone Reano (ORCID: https://orcid.org/0000-0002-5059-3620)
- Emilio Hirsch (ORCID: https://orcid.org/0000-0002-9073-6024)
- Elia Angelino (ORCID: https://orcid.org/0000-0002-4305-0863)
- Fabiana Ferrero (ORCID: https://orcid.org/0009-0000-5097-6640)
- Camilla Pezzini (ORCID: https://orcid.org/0009-0007-3567-3925)
- Monica Nicolau (ORCID: https://orcid.org/0009-0004-6534-1874)
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- National Institutes of Health (US)
- University of Padua (IT)
- University of Milan (IT)
- Discovery Institute (US)
- Veneto Institute of Molecular Medicine (IT)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Institute of Oncology Research (CH)
- Italian institute for Genomic Medicine (IT)
- IRCCS Ospedale San Raffaele (IT)
- University of Turin (IT)
- Università della Svizzera italiana (CH)
- University of Genoa (IT)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1038/s42255-025-01397-5
- Citations
- 4
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.22