๐ค Authors: Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D'Anna, Nicolรฒ Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corร , Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani
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.
