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Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

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 _2A/_2C-adrenoceptor knockout (_2A/_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 _2A/_2CARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, _2A/_2CARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, _2A/_2CARKO mice displayed increased phospho-Ser¹⁶-PLN (76%) and phospho-Ser²⁸⁰⁹-RyR (49%). ET in _2A/_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