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

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 mitochon

SUBMITTER: Angelino E 

PROVIDER: S-EPMC12727542 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature