Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

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Abstract
The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca2+ handling abnormalities and whether ET would improve VF of mice lacking α2A- and α2C-adrenoceptors (α2A/α2CARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic α2A/α2CARKO mice in a C57BL/J genetic background (5–7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser16-PLN, phospho-Thr17-PLN, phosphatase 1 (PP1), and Na+-Ca2+ exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. α2A/α2CARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in α2A/α2CARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in α2A/α2CARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser16-PLN (63%), phospho-Thr17-PLN (211%) in α2A/α2CARKO mice. Furthermore, ET restored NCX and PP1 expression in α2A/α2CARKO to untrained WT mice levels. Thus, we provide evidence that Ca2+ handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca2+ handling proteins.