Mechanisms underlying exercise-mediated rescue of cachexia

Cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support (1). Cachexia correlates with poor prognosis and worsens patients quality of life. Indeed, cancer cachexia accounts for about 20% of cancer patient’ s deaths. Recent studies showed that physical activity after cancer diagnosis ameliorates the prognosis, although the underling mechanisms are still poorly understood. 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 were reversed by exercise, including body weight loss, muscle atrophy and fatigue, ultimately leading to increased survival. These data suggest a potential role for the use of exercise mimetics to counteract cachexia. To test this hypothesis, we treated C26-bearing mice with AICAR, an analog of AMP, able to activate AMPK-mediated pathways, thus mimicking endurance exercise adaptations in skeletal muscle (2). Strikingly, C26-bearing AICAR treated mice looked healthier, lost significantly less body and muscle weight and showed reduced expression of atrogenes in respect to vehicle treated mice. Since both exercise (3) and AICAR (4) are known to trigger autophagy in skeletal muscle, we tested if induction of autophagy by rapamycin (5), an inhibitor of mTOR, could ameliorate cancer cachexia in C26-bearing mice. As for AICAR treatment, C26-bearing mice treated with rapamycin looked healthier and lost significantly less body and muscle weight than C26-bearing mice treated with vehicle. Remarkably, neither AICAR nor rapamycin treatment affected tumor mass growth. As shown by LC3 II and p62 accumulation cachectic muscles showed induced autophagy but compromised autophagic flux, in agreement with (6), while both AICAR and rapamycin treatments allowed autophagic flux to proceed in C26-bearing mice. Strikingly, a significant accumulation of p62, indicative of compromised autophagic flux, was also seen in human skeletal muscle biopsies from patients affected with colorectal cancer compared to healthy controls. We demonstrated that impairment of autophagic flux is a major contributor of muscle wasting in C26-bearing mice. Indeed, by promoting autophagy with two different drugs we could ameliorate muscle homeostasis in cachectic mice. We propose that exercise counteracts cancer cachexia likely by inducing autophagy thereby revealing a potential use of exercise mimetics or autophagy triggering drugs to improve cancer cachexia.