Mechanisms underlying exercise-mediated rescue of cachexia

Recent studies showed that physical activity after cancer diagnosis ameliorates the prognosis, although the underling mechanisms are stili poorly understood. Cachexia, experienced by most cancer patients, is a negative prognostic factor, interfering with therapy and worsening quality of life. With the aim to delineate the pathways involved in exercise-mediated rescue of cachexia, we investigated the effects of spontaneous physical activity (wheel running) in colon carcinoma (C26)-bearing mice. All major diagnostic criteria for cachexia are reversed by exercise, including rescue of body weight, muscle atrophy and fatigue, ultimately leading to increased survival. In order to assess whether muscle contraction plays a role in the exercise-mediated rescue of cachexia, we denervated one limb of (C26)-bearing mice and assessed muscle mass following spontaneous wheel running. Interestingly, exercise exerts positive effects on (C26)-bearing mice muscle mass independently from denervation, suggesting cross-education induced by exercise on the denervated muscle. At the molecular level, exercise promotes protein synthesis, by mTOR activation, and attenuates protein degradation, by downregulating Atrogin1, in muscle from C26-bearing mice. Despite muscle damage in cachexia, satellite cells fail to fuse into muscle fibers, due to defective down-regulation of Pax7 expression. We showed that exercise rescues proper Pax7 expression levels in cachexia, which in turn may release the block of satellite celi differentiation. We propose that exercise counteracts muscle wasting through a systemic effect, by both inhibiting catabolic pathways and favouring satellite celi recruitment into muscle fibers, unveiling a novel mechanism of exercise-mediated beneficiai effects on cachexia