Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Author(s)

Campos, Juliane C. ^[1] ; Queliconi, Bruno B. ^[2] ; Dourado, Paulo M. M. ^[3] ; Cunha, Telma F. ^[4] ; Zambelli, Vanessa O. ^[5] ; Bechara, Luiz R. G. ^[4] ; Kowaltowski, Alicia J. ^[2] ; Brum, Patricia C. ^[4] ; Mochly-Rosen, Daria ^[6] ; Ferreira, Julio C. B. ^{[1, 6]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Heart, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo - Brazil

^[5] Butantan Inst, Sao Paulo - Brazil

^[6] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA

• Document type: Journal article
• Source: PLoS One; v. 7, n. 12 DEC 27 2012.
• Web of Science Citations: 44

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 nonpharmacological tool for heart failure therapy. (AU)

• FAPESP's process: 12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development
• Grantee: Julio Cesar Batista Ferreira
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 10/00028-4 - Characterization of mitochondrial fusion and fission in heart failure: effects of exercise training
• Grantee: Patricia Chakur Brum
• Support type: Regular Research Grants
• FAPESP's process: 09/12349-2 - Characterization of mitochondrial function and dynamics in cardiac dysfunction-induced myocardial infarction in rats
• Grantee: Juliane Cruz Campos
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 09/18546-4 - Protein quality control in heart failure: role of different protein kinase C isozymes
• Grantee: Patricia Chakur Brum
• Support type: Regular Research Grants