Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer.

Eva Pigna,Zhenlin Li,Ugo Carraro,Valentina Di Felice,Sandra Zampieri,Viviana Moresi,Emanuele Berardi,Paola Aulino,Mario Gruppo,Dario Coletti,Emanuele Rizzuto,Filippo Macaluso,Mathias Mericskay,Sergio Adamo,Rosario Barone,Helmut Kern,Stefano Merigliano,Marco Rocchi

doi:10.1038/srep26991

Abstract

Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed.

Highlights

Cancer is a major, worldwide health problem that is responsible for one in four deaths[1,2]
By quantifying Evans’ Blue dye (EBD) uptake by two different muscles, which is considered a marker of cell impairment, we confirmed that the C26 tumor induces muscle fiber damage, and we found that wheel running (WR) per se did not damage or interact with tumor-induced muscle fiber damage (Supplementary Fig. S1)
WR improved muscle function in C26-bearing mice: the extensor digitorum longus (EDL) muscle, a muscle that we previously found to be affected in cancer cachexia[29], exhibited a shorter fatigue time in C26-bearing control mice than in non-C26-bearing control mice, while no differences were detected in WR C26-bearing mice (Fig. 1d)

Summary

Introduction

Worldwide health problem that is responsible for one in four deaths[1,2]. Increases survival in cancer patients and improves their quality of life[7], prescribing exercise to these patients is not a straightforward task. It is, of paramount importance to identify potential pharmacological treatments that may be able to mimic the effects of exercise in pathological conditions. A major cause of patient mortality, morbidity and low quality of life, including exercise intolerance, is cancer-associated cachexia. Cancer cachexia is probably the most severe form of muscle atrophy and is associated with increased morbidity and mortality[10]. Since exposing tumor-bearing mice, and possibly even humans, to exercise protocols might be deleterious, pharmacological alternatives to physical activity are needed

Methods

Results

Conclusion