Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Penna, Fabio¹  Ballaro, Riccardo¹  Martinez-Cristobal, Paula^2,3,5  Sala, David²  Sebastian, David^2,3,5  Busquets, Silvia³  Muscaritoli, Maurizio⁴  Argiles, Josep M.³  Costelli, Paola¹  Zorzano, Antonio^2,3,5 

[1] Univ Torino, Dept Clin & Biol Sci, Turin, Italy

[2] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona, Spain

[3] Univ Barcelona, Fac Biol, Dept Bioquim & Biomed Mol, Barcelona, Spain

[4] Sapienza Univ, Dept Clin Med, Rome, Italy

[5] Inst Salud Carlos Ill, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain

关键词: autophagy;    cancer cachexia;    muscle wasting;    mitochondria;    mitophagy;   

DOI  :  10.1016/j.jmb.2019.05.032

来源: Elsevier

【 摘 要 】

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 beta 2-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. (C) 2019 Elsevier Ltd. All rights reserved.

【 授权许可】

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