Impairment of cAMP/PKA/CREB1 signaling in skeletal muscle drives metabolic dysfunction in cancer cachexia: The key role of PDE4D, a cAMP-hydrolyzing phosphodiesterase

Cancer-associated cachexia affects most of cancer patients and is characterized by a profound loss of skeletal muscle mass and function. To date, effective pharmacological strategies to halt or reverse cachexia progression are still lacking in clinical practice, significantly compromising both patients’ quality of life and overall survival. Emerging evidence suggests that, in the early stages of cachexia, a coordinated transcriptional program regulating mitochondrial biogenesis, dynamics, and function is suppressed in skeletal muscle. This suppression contributes to mitochondrial dysfunction and accelerates muscle wasting. Currently, the precise mechanisms underlying the decline in muscle oxidative capacity are still poorly understood. In this study, we combined transcriptomic analysis, chromatin immunoprecipitation sequencing (ChIP-seq), Ser/Thr kinase activity profiling, and mitochondrial respirometry in the skeletal muscle of tumor-bearing mice to dissect the molecular mechanisms underlying mitochondrial dysfunction in cachexia. Here we report that tumor-derived factors impair skeletal muscle PKA activity and the transcriptional function of CREB1, thus leading to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. This results in a marked reduction of mitochondrial mass and respiratory capacity in skeletal muscle of cachectic mice. Importantly, restoration of cAMP/PKA/CREB1 signaling in vivo through pharmacological inhibition of the cAMP-hydrolyzing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, replenishes mitochondrial content, significantly improves mitochondrial respiration in the skeletal muscle, and ultimately results in improved muscle strength of tumor-bearing mice. Interestingly, among PDE4 isoforms, PDE4D emerged as a key mediator of this process. Collectively, these findings propose PDE4(D) inhibition as a promising therapeutic strategy to preserve muscle mitochondrial integrity and function, offering a means to counteract the metabolic collapse that drives muscle wasting in cancer cachexia