Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia PMID: 41224958

ADC Targets in Oncology

2026-04-10

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.

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.