Exercise training restores cardiac protein quality control in heart failure

PLoS One. 2012;7(12):e52764. doi: 10.1371/journal.pone.0052764. Epub 2012 Dec 27.

Abstract

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H₂O₂ release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H₂O₂ resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca²⁺-induced permeability transition and reduced H₂O₂ release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a non-pharmacological tool for heart failure therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism
  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Exercise Therapy*
  • Heart Failure / metabolism
  • Heart Failure / therapy*
  • Hydrogen Peroxide / metabolism
  • Male
  • Mitochondria, Heart / metabolism
  • Muscle Proteins / physiology*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / therapy
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Oligopeptides / pharmacology
  • Oxidation-Reduction
  • Oxidative Stress
  • Oxygen Consumption
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • Rats
  • Rats, Wistar
  • Running

Substances

  • Aldehydes
  • Muscle Proteins
  • Oligopeptides
  • Proteasome Inhibitors
  • Hydrogen Peroxide
  • Proteasome Endopeptidase Complex
  • 4-hydroxy-2-nonenal
  • Calcium
  • epoxomicin