Pde 4 induction mediates B-adrenergic dysfunction and contributes to skeletal muscle wasting during cancer cachexia

Cancer cachexia is a multifactorial syndrome characterized by pronounced skeletal muscle wasting whose driving mechanisms are currently incompletely defined. Dysfunctional oxidative metabolism and disruption of key components of the neuromuscular junction (NMJ) are among the main mechanisms that contribute to loss of muscle mass and function during cancer cachexia. Under physiological conditions, sympathetic nervous system uncovers a well-established role in sustaining skeletal muscle mass, oxidative metabolism, NMJ integrity, and muscle function through the release of noradrenaline and the activation of the adrenergic signaling. Our in vitro data in C2C12 myoblasts, demonstrate that both colon carcinoma C26 and Lewis lung carcinoma tumor condition medium, two well-established pro-cachectic models, impair the adrenergic-dependent activation of cAMP/PKA/CREB pathway through the induction of phosphodiesterases 4 (Pde4). Moreover, transcriptomic analysis, performed on skeletal muscle of C26-bearing mice, revealed an altered expression of cAMP signaling components, together with the selective induction of Pde4b, Pde4c and Pde4d. Treatment with the Pde4-inhibitor rolipram of C26-bearing mice results in a partial protection against skeletal muscle atrophy, together with improved NMJ structure and muscle strength. Interestingly, RNAseq analysis reveals that rolipram treatment results in an extensive modulation of the autophagic, protein catabolic and oxidative metabolism pathways. Altogether, these findings suggest that targeting the defective cAMP axis, through the pharmacological inhibition of Pde4, could represent a strategy to revert muscle wasting in cancer cachexia.