Autophagic flux restoration by exercise or pharmacological treatment counteracts cancer cachexia

Recent studies correlate physical activity with a better prognosis of cachectic patients, although the underlying mechanisms are still poorly understood. However, physical activity spontaneously declines in cancer patients and that they do not exercise enough even after tumor resection. Although exercise non only increases survival but also ameliorates quality of life among cancer patients, prescribing exercise to cancer patients is not a straightforward endeavor. For these reasons, finding it potential pharmacological treatments that can substitute for exercise in pathological conditions is of paramount importance. With the aim to identify the pathways involved in physical activity-mediated treatment of cachexia, we investigated the effects of voluntary exercise (wheel running) in colon carcinoma (C26) bearing mice (1). C26-bearing mice performed wheel running even with overt cachexia, albeit to a lesser extent than controls (2). Voluntary wheel running counteracted body weight loss, skeletal muscle atrophy and fatigue, the induction of atrogenes and the blockage of muscle autophagic flux observed in cachexia, ultimately leading to increased survival of C26 bearing mice. Paradoxically, body weight loss, and the correlated muscle wasting, were not always associated with death in C26-bearing mice, suggesting the need to investigate additional mechanisms. Noticeably, autophagic flux is hampered in skeletal muscle of colon carcinoma patients as well as in C26-bearing mice. To test if restoration of the autophagic flux limits cancer cachexia, we treated C26 bearing mice with either 5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide (AICAR), or rapamycin, in the absence of exercise. Both drugs counteracted cancer cachexia and restored the autophagic flux in skeletal muscle. In conclusion, our findings reveal that impairment of the autophagic flux is a major contributor to muscle wasting in cancer cachexia, thereby suggesting the potential use of autophagy-triggering drugs for treatment. In addition, we propose that voluntary wheel running help to counteract cancer cachexia by restoring the autophagic flux, as well.