Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training

Abstract

Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HF-induced skeletal myopathy. However, little is known about the influence of SH on skeletal muscle morphology and metabolism in a setting of developing HF, taking into consideration muscles with different fiber compositions. The contribution of SH on exercise tolerance and skeletal muscle morphology and biochemistry was investigated in 3- and 7-mo-old mice lacking both α2A- and α2C-adrenergic receptor subtypes (α2A/α2CARKO mice) that present SH with evidence of HF by 7 mo. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, α2A/α2CARKO mice were exercised from 5 to 7 mo of age. At 3 mo, α2A/α2CARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of α2A/α2CARKO mice displayed hypertrophy and fiber type shift (IIA → IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, α2A/α2CARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished α2A/α2CARKO mouse exercise tolerance to 7-mo-old wild-type levels and prevented muscular atrophy and capillary rarefaction associated with reduced oxidative stress. Collectively, these data provide direct evidence that SH is a major factor contributing to skeletal muscle morphological changes in a setting of developing HF. ET prevented skeletal muscle myopathy in α2A/α2CARKO mice, which highlights its importance as a therapeutic tool for HF.