Journal of Applied Physiology AJP: Cell Physiology
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J Appl Physiol 104: 103-109, 2008. First published November 1, 2007; doi:10.1152/japplphysiol.00493.2007
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Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

Alessandra Medeiros,1 Natale P. L. Rolim,1 Rodrigo S. F. Oliveira,1 Kaleizu T. Rosa,2 Katt C. Mattos,1 Dulce E. Casarini,3 Maria Claúdia Irigoyen,2 Eduardo M. Krieger,2 José Eduardo Krieger,2 Carlos Eduardo Negrão,1,2 and Patricia C. Brum1

1School of Physical Education and Sport, University of São Paulo; 2Heart Institute (InCor), School of Medicine, University of São Paulo; and 3Department of Medicine, Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil

Submitted 7 May 2007 ; accepted in final form 30 October 2007

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca2+ handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic {alpha}2A/{alpha}2C-adrenoceptor knockout ({alpha}2A/{alpha}2CARKO) mice with C57BL6/J genetic background (3–5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser2809-RyR, sarcoplasmic reticulum Ca2+ ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLN), phospho-Ser16-PLN, and phospho-Thr17-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and {alpha}2A/{alpha}2CARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, {alpha}2A/{alpha}2CARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, {alpha}2A/{alpha}2CARKO mice displayed increased phospho-Ser16-PLN (76%) and phospho-Ser2809-RyR (49%). ET in {alpha}2A/{alpha}2CARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser16-PLN (30%) while it restored the expression of phospho-Ser2809-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca2+ handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.

calcium handling proteins; ventricular function; plasma norepinephrine levels; cardiomyopathy; exercise conditioning



Address for reprint requests and other correspondence: P. C. Brum, Escola de Educação Física e Esporte da Universidade de São Paulo, Departamento de Biodinâmica do Movimento do Corpo Humano Av. Professor Mello Moraes, 65 Butantã, São Paulo 05508-900, Brazil (e-mail: pcbrum{at}usp.br)




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