Repeated eccentric contractions positively regulate muscle oxidative metabolism and protein synthesis during cancer cachexia in mice.

: Cancer-induced wasting is accompanied by disruptions to muscle oxidative metabolism and protein turnover that have been associated with systemic inflammation, whereas exercise and stimulated muscle contractions can positively regulate muscle protein synthesis and mitochondrial homeostasis. In preclinical cancer cachexia models a single bout of eccentric contractions (ECC) can induce protein synthesis while repeated ECC bouts prevent myofiber atrophy. The cellular mechanisms providing this protection from atrophy have not been resolved. Therefore, the purpose of this study was to determine if repeated stimulated eccentric contraction bouts effect basal muscle oxidative metabolism and protein synthesis during cancer cachexia, and if these changes were associated with plasma IL-6 levels. Male ApcMin/+ (MIN; N=10) mice initiating cachexia and healthy C57BL/6 (B6; N=11) controls performed repeated ECC bouts over 2 weeks. MIN mice exhibited body weight loss and elevated plasma IL-6 prior to and during repeated ECC bouts. Control MIN muscle demonstrated disrupted signaling related to inflammation, oxidative capacity and protein synthesis regulation, which were all improved by repeated ECC bouts. With cachexia plasma IL-6 levels were negatively correlated with myofiber cross-sectional area, oxidative capacity and protein synthesis. Interestingly, ECC improvements in these outcomes were positively correlated with plasma IL-6 levels in MIN mice. There was also a positive relationship between muscle oxidative capacity and protein synthesis following repeated ECC bouts in MIN mice. Collectively, repeated ECC bouts altered the cachectic muscle phenotype independent to systemic wasting, and there was a strong association between muscle oxidative capacity and protein synthesis in this adaptive response.