Impaired cAMP/CREB1 signaling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia [ChIP-seq]

Skeletal muscle wasting is a hallmark of cachexia, a cancer-associated syndrome that severely affects patients' quality of life. Emerging evidence indicates that at early stages of cachexia a large transcriptional network of genes involved in mitochondrial biogenesis, dynamics, and function is down-regulated in skeletal muscle, thus leading to mitochondrial dysfunction and muscle wasting. Here, by exploiting in vivo and in vitro cachexia models, we report that i) tumor-induced impairment of cAMP/CREB1 signaling in skeletal muscle contributes to the downregulation of the transcriptional network sustaining mitochondrial function; ii) the cAMP-hydrolyzing phosphodiesterases 4D (PDE4D), whose transcript variants are deregulated in cachectic muscle, mediates tumor-induced cAMP signaling impairment in vitro. iii) boosting cAMP signaling by targeting PDE4 in vivo rescues mitochondrial-related gene expression, mitochondrial dysfunction, and mitigates muscle wasting. Collectively, we identified tumor-induced impairment of cAMP/CREB1 signaling as a driver of skeletal muscle mitochondrial dysfunction occurring during cancer cachexia. Overall design: ChIP-seq profiling of phosphorylated CREB1 in gastrocnemius muscle from C26-injected and control mice.