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 is characterized by severe muscle atrophy and weakness, accounting for poor prognosis and worsening 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 rescue of body weight, 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 that is capable of activating AMPK-mediated pathways, thus mimicking endurance exercise adaptations in skeletal muscle. Strikingly, AICAR treated mice looked healthier, lost significantly less body and muscle weight and show reduced expression of atrogenes in respect to vehicle treated mice. We propose that physical activity counteracts cachexia and reveal a potential use of exercise mimetics to ameliorate patient muscle wastin