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 Ca(2+) handling abnormalities and whether ET would improve VF of mice lacking alpha(2A)- and alpha(2C)-adrenoceptors (alpha(2A)/alpha(2C)ARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO 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 Ca(2+) ATPase (SERCA2), phospholamban (PLN), phospho-Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), and Na(+)-Ca(2+) exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. alpha(2A)/alpha(2C)ARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in alpha(2A)/alpha(2C)ARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in alpha(2A)/alpha(2C)ARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser(16)-PLN (63%), phospho-Thr(17)-PLN (211%) in alpha(2A)/alpha(2C)ARKO mice. Furthermore, ET restored NCX and PP1 expression in alpha(2A)/alpha(2C)ARKO to untrained WT mice levels. Thus, we provide evidence that Ca(2+) 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 Ca(2+) handling proteins.

Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

“…At 7 months of age, when α 2A /α 2C ARKO mice display severe HF, exercise training restored cardiac NCX expression levels, and increased SERCA2, and phosphorylated phospholamban expression levels at both residues Ser 16 and Thr 17 , which resulted in improved left ventricular function. These findings suggest that the improvement in intracellular Ca 2+ regulation is a molecular mechanism underlying the benefits of exercise training for overall ventricular function in severe HF (18).…”

“…In this context, we have suggested that exercise training would improve cardiac function in HF animals by, changing, at least in part, the expression of proteins involved in cardiac Ca 2+ homeostasis. We found that exercise training significantly increased fractional shortening toward normal levels and improved the net balance of cardiac Ca 2+ proteins involved in Ca 2+ transsarcolemmal flux and sarcoplasmic reticulum Ca 2+ reuptake in a genetic model of sympathetic hyperactivity-induced HF based on α 2A and α 2C adrenoceptor gene inactivation in mice (α 2A / α 2C ARKO) (18). At 7 months of age, when α 2A /α 2C ARKO mice display severe HF, exercise training restored cardiac NCX expression levels, and increased SERCA2, and phosphorylated phospholamban expression levels at both residues Ser 16 and Thr 17 , which resulted in improved left ventricular function.…”

“…www.bjournal.com.br Braz J Med Biol Res 44(9) 2011 exercise training significantly reduced sympathetic tone with a remarkable cardiac anti-remodeling effect in HF mice (18). Indeed, exercise training reduced cardiac angiotensin II levels by reducing local renin-angiotensin system activation in HF α 2A / α 2C ARKO mice (21).…”

“…These effects include reduction of sympathetic outflow in exercised humans (14,15) and animals (16)(17)(18) with HF. The sympathetic toxicity of cardiac (17)(18)(19)(20)(21) and skeletal (22)(23)(24) muscles in HF is also reduced by exercise training. Since morbidity and mortality in cardiovascular disease are often associated with increases of sympathetic nerve activity, exercise training becomes a potent nonpharmacological strategy for HF therapy.…”

“…In animal models of HF, studies using invasive methodologies demonstrated improved cardiac function by aerobic exercise training (17,18), which led to further studies focusing on the mechanisms underlying these beneficial effects. Ventricular function is tightly coupled to Ca 2+ transients in the heart.…”