Effects of contraction and feeding on skeletal muscle protein synthesis during the initiation of cachexia

Abstract

Muscle contraction and feeding are potent regulators of skeletal muscle protein synthesis. Cancer cachexia can suppress muscle protein synthesis through Akt/mTORC1 signaling suppression. Cachexia also suppresses acute contraction‐induced muscle protein synthesis. However, the cancer environment’s impact on the combined feeding and contraction activation of protein synthesis during the initiation of cachexia is not well understood. Therefore, we examined the cancer environment’s effect on the muscle protein synthesis response to an acute bout of muscle contraction with and without feeding.METHODSMale C57BL/6J (B6; N=36) were injected with 1 x 106 Lewis Lung Carcinoma (LLC) cells or PBS subcutaneously in the right flank and were monitored for up to 30 days. Following an overnight 12hr fast, mice were given ad libitum access to a food pellet for 1hr (fed) or fasted for an additional hour (fast). Subsequently, mice were subjected to low‐frequency electrical stimulation (LFES) for 30 minutes and sacrificed 3hrs post. Puromycin was injected 30min before sacrifice for protein synthesis measurements. Gastrocnemius muscle was examined for protein expression and values normalized to the contralateral limb.RESULTSIn PBS mice, LFES induced rpS6 (9.5‐fold) and protein synthesis (4.7‐fold). LFES induced rpS6 (1.7‐fold) and protein synthesis (0.9‐fold) in LLC mice. Overall, rpS6 and protein synthesis were lower in the LLC mice compared to PBS. Feeding increased muscle rpS6 and protein synthesis in PBS mice (p<0.001) but not in LLC (p=0.821 and p=0.642) mice. Feeding and LFES synergistically induce rpS6 and protein synthesis in PBS mice; however, this was not present in LLC mice.CONCLUSIONWe report that contraction’s ability to increase muscle protein synthesis is suppressed in mice initiating cachexia. The ability for feeding to increase muscle protein synthesis is also suppressed in mice initiating cachexia. Notably, the combined effects of feeding and contraction were insufficient to synergistically improve muscle protein synthesis as in healthy mice. Future studies should determine why feeding was not sufficient to induce muscle protein synthesis in mice initiating cachexia.