Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function

Publication date: Available online 28 May 2019Source: Journal of Molecular BiologyAuthor(s): Fabio Penna, Riccardo Ballarò, Paula Martinez-Cristobal, David Sala, David Sebastian, Silvia Busquets, Maurizio Muscaritoli, Josep M. Argilés, Paola Costelli, Antonio ZorzanoAbstractCancer 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.Graphical abstract
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research