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Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function
1 - Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
2 - Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
3 - Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
4 - Department of Clinical Medicine, Sapienza University, Rome, Italy
5 - Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Correspondence to Fabio Penna and Antonio Zorzano: [email protected], [email protected] https://doi.org/10.1016/j.jmb.2019.05.032
Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers, although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.
Cancer-associated cachexia is a multifactorial syndrome characterized by anorexia and body weight loss, mainly due to muscle and fat wasting . Cachexia and in particular skeletal muscle loss significantly impair cancer patients' quality of life and tolerance to anti-neoplastic treatments, eventually reducing survival. Despite the relevance of this syndrome to cancer patient outcome, anti-cachexia treatments are still lacking. The currently available standard of care for cachectic cancer patients is limited to nutritional support, while specific treat-ments aimed at counteracting muscle wasting are under investigation and no clinical trial proved effective so far.