Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 431, Issue 15, Pages 2674-2686Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2019.05.032
Keywords
autophagy; cancer cachexia; muscle wasting; mitochondria; mitophagy
Categories
Funding
- la Caixa/IRB International Ph.D. Programme
- University of Torino
- MINECO [SAF2016-75246R]
- Generalitat de Catalunya [2014SGR48]
- CIBERDEM (Instituto de Salud Carlos III)
- INFLAMES (Instituto de Salud Carlos III) [PIE-14/00045]
- AIRC [IG 2018-ID. 21963]
- ICREA Academia (Generalitat de Catalunya)
- MINECO through the Centres of Excellence Severo Ochoa Award
- CERCA Programme of the Generalitat de Catalunya
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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.
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