Exercise training reverses cancer cachexia-induced decrease in muscle COPS2/TRIP15/ALIEN

The mechanisms underlying exercise-induced effects in the skeletal muscle during cancer cachexia progression have not been fully described. Here, we tested the hypothesis that different exercise training protocols could attenuate metabolic impairment in a severe model of cancer cachexia. Moderate-intensity training (MIT) and high-intensity interval training (HIIT) improved running capacity and prolonged lifespan in tumor-bearing rats. HIIT also reduced oxidative stress and reestablished muscle contractile function. An unbiased proteomics screening revealed that COP9 signalosome complex subunit 2 (COPS2), also known as thyroid receptor interacting protein 15 (TRIP15) or ALIEN, is one of the most downregulated proteins at the early stage of cancer cachexia progression. HIIT restored COPS2/TRIP15/ALIEN protein expression to the control levels. Moreover, lung cancer patients with low endurance capacity had lower muscle COPS2/TRIP15/ALIEN protein content compared to age- and sex-matched control subjects. We further established an in vitro model of cancer-induced muscle wasting using tumor cells-conditioned media to explore the potential protective role of COPS2/TRIP15/ALIEN for myotubes homeostasis. This in vitro model indicate that tumor cells produce factors that directly affect myotube metabolism, but COPS2/TRIP15/ALIEN overexpression is not able to fully reestablish metabolic homeostasis and protein content in myotubes incubated with tumor cells-conditioned media. The current study provides new insight into the role of exercise training as a co-therapy for cancer cachexia and uncovers COPS2/TRIP15/ALIEN as a novel potential target for cancer cachexia.