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

1 School of Physical Education and Sport, University of São Paulo; 2 Heart Institute (InCor), School of Medicine, University of São Paulo; and 3 Department 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 Ca 2+ 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 / 2C ARKO) 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-Ser 2809 -RyR, sarcoplasmic reticulum Ca 2+ ATPase (SERCA2), Na + /Ca 2+ exchanger (NCX), phospholamban (PLN), phospho-Ser 16 -PLN, and phospho-Thr 17 -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 / 2C ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, 2A / 2C ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, 2A / 2C ARKO mice displayed increased phospho-Ser 16 -PLN (76%) and phospho-Ser 2809 -RyR (49%). ET in 2A / 2C ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser 16 -PLN (30%) while it restored the expression of phospho-Ser 2809 -RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca 2+ 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,