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Autophagy. 2017 Aug 3;13(8):1304-1317. doi: 10.1080/15548627.2017.1325062.

Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure.

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a Department of Anatomy , Institute of Biomedical Sciences, University of Sao Paulo , Sao Paulo , Brazil.
b The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center , Cedars-Sinai Medical Center , Los Angeles , CA , USA.
c Departamento de Bioquímica , Instituto de Química, Universidade de São Paulo , Sao Paulo , Brazil.
d Heart Institute , University of Sao Paulo , Sao Paulo , Brazil.
e School of Physical Education and Sport , University of Sao Paulo , Sao Paulo , Brazil.
f Butantan Institute , Sao Paulo , Brazil.
g Department of Physiology and Biophysics , Federal University of Minas Gerais , Belo Horizonte , Brazil.
h Department of Chemical and Systems Biology , Stanford University School of Medicine , Stanford , CA , USA.


We previously reported that facilitating the clearance of damaged mitochondria through macroautophagy/autophagy protects against acute myocardial infarction. Here we characterize the impact of exercise, a safe strategy against cardiovascular disease, on cardiac autophagy and its contribution to mitochondrial quality control, bioenergetics and oxidative damage in a post-myocardial infarction-induced heart failure animal model. We found that failing hearts displayed reduced autophagic flux depicted by accumulation of autophagy-related markers and loss of responsiveness to chloroquine treatment at 4 and 12 wk after myocardial infarction. These changes were accompanied by accumulation of fragmented mitochondria with reduced O2 consumption, elevated H2O2 release and increased Ca2+-induced mitochondrial permeability transition pore opening. Of interest, disruption of autophagic flux was sufficient to decrease cardiac mitochondrial function in sham-treated animals and increase cardiomyocyte toxicity upon mitochondrial stress. Importantly, 8 wk of exercise training, starting 4 wk after myocardial infarction at a time when autophagy and mitochondrial oxidative capacity were already impaired, improved cardiac autophagic flux. These changes were followed by reduced mitochondrial number:size ratio, increased mitochondrial bioenergetics and better cardiac function. Moreover, exercise training increased cardiac mitochondrial number, size and oxidative capacity without affecting autophagic flux in sham-treated animals. Further supporting an autophagy mechanism for exercise-induced improvements of mitochondrial bioenergetics in heart failure, acute in vivo inhibition of autophagic flux was sufficient to mitigate the increased mitochondrial oxidative capacity triggered by exercise in failing hearts. Collectively, our findings uncover the potential contribution of exercise in restoring cardiac autophagy flux in heart failure, which is associated with better mitochondrial quality control, bioenergetics and cardiac function.


autophagy; bioenergetics; cardiovascular disease; exercise; mitochondrial fission-fusion machinery; mitochondrial quality control

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