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

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 α_2A- and α_2C-adrenoceptors (α_2A/α_2CARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic α_2A/α_2CARKO 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. α_2A/α_2CARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in α_2A/α_2CARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in α_2A/α_2CARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser¹⁶-PLN (63%), phospho-Thr¹⁷-PLN (211%) in α_2A/α_2CARKO mice. Furthermore, ET restored NCX and PP1 expression in α_2A/α_2CARKO 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.