Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure

Abstract

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 O consumption, elevated HO release and increased Ca-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.

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“…Considering that autophagy is impaired in neurogenic myopathy, we next set out to determine whether the re-establishment of autophagic flux is sufficient to improve skeletal muscle proteostasis and counteract SNC-induced skeletal muscle damage. We have recently demonstrated that exercise training is able to restore the autophagic flux in failing hearts contributing to better disease prognosis 21 . To evaluate the effects of exercise training in autophagy in a model of neurogenic myopathy, rats were submitted to 4 weeks of moderate running training on a treadmill prior to SNC surgery.…”

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What and How Can Physical Activity Prevention Function on Parkinson’s Disease?

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