Aerobic exercise training improves skeletal muscle function and Ca²⁺ handling-related protein expression in sympathetic hyperactivity-induced heart failure

Abstract

The cellular mechanisms of positive effects associated with aerobic exercise training on overall intrinsic skeletal muscle changes in heart failure (HF) remain unclear. We investigated potential Ca2+ abnormalities in skeletal muscles comprising different fiber compositions and investigated whether aerobic exercise training would improve muscle function in a genetic model of sympathetic hyperactivity-induced HF. A cohort of male 5-mo-old wild-type (WT) and congenic alpha2A/alpha2C adrenoceptor knockout (ARKO) mice in a C57BL/6J genetic background were randomly assigned into untrained and trained groups. Exercise training consisted of a 8-wk running session of 60 min, 5 days/wk (from 5 to 7 mo of age). After completion of the exercise training protocol, exercise tolerance was determined by graded treadmill exercise test, muscle function test by Rotarod, ambulation and resistance to inclination tests, cardiac function by echocardiography, and Ca2+ handling-related protein expression by Western blot. alpha2A/alpha2CARKO mice displayed decreased ventricular function, exercise intolerance, and muscle weakness paralleled by decreased expression of sarcoplasmic Ca2+ release-related proteins [alpha1-, alpha2-, and beta1-subunits of dihydropyridine receptor (DHPR) and ryanodine receptor (RyR)] and Ca2+ reuptake-related proteins [sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)1/2 and Na+/Ca2+ exchanger (NCX)] in soleus and plantaris. Aerobic exercise training significantly improved exercise tolerance and muscle function and reestablished the expression of proteins involved in sarcoplasmic Ca2+ handling toward WT levels. We provide evidence that Ca2+ handling-related protein expression is decreased in this HF model and that exercise training improves skeletal muscle function associated with changes in the net balance of skeletal muscle Ca2+ handling proteins.

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

“…This ultimately leads to improved skeletal muscle function (23). Regarding skeletal muscle atrophy, even aerobic exercise training is able to re-establish soleus and plantaris trophicity in our sympathetic hyperactivityinduced HF mouse model (22,23). This is somewhat surprising since resistance and not aerobic exercise training swings the protein synthesis/degradation balance in favor of protein synthesis.…”

“…Interestingly, we have demonstrated that aerobic exercise training improves the net balance of skeletal muscle Ca 2+ -handling proteins in mice (60). Moreover, exercise training restores the expression levels of proteins involved in sarcoplasmic Ca 2+ release and reuptake in soleus and plantaris muscles from HF mice (23). This ultimately leads to improved skeletal muscle function (23).…”

“…Moreover, exercise training restores the expression levels of proteins involved in sarcoplasmic Ca 2+ release and reuptake in soleus and plantaris muscles from HF mice (23). This ultimately leads to improved skeletal muscle function (23). Regarding skeletal muscle atrophy, even aerobic exercise training is able to re-establish soleus and plantaris trophicity in our sympathetic hyperactivityinduced HF mouse model (22,23).…”

“…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 severe HF rats, decreased skeletal muscle sarcoplasmic Ca 2+ levels were associated with a reduced rate of sarcoplasmic reticulum Ca 2+ release (58) and reuptake (59). This response is partially explained by reduced expression of proteins involved in intracellular Ca 2+ homeostasis in skeletal muscles consisting of different fiber types such as soleus and plantaris muscles (predominantly oxidative and glycolytic muscles, respectively) (23). Interestingly, we have demonstrated that aerobic exercise training improves the net balance of skeletal muscle Ca 2+ -handling proteins in mice (60).…”