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 _2A/_2C AR subtypes (_2A/_2C ARKO) that present SH with evidence of HF by 7 months. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, _2A/_2C ARKO were exercised from 5 to 7 months of age. At 3 months, _2A/_2C ARKO showed no signs of HF and preserved exercise tolerance and muscular noradrenaline with no changes in soleus morphology. In contrast, plantaris muscle of _2A/_2C ARKO displayed hypertrophy and fiber type shift (IIAIIX) paralleled by capillary rarefaction, increased hexokinase activity and oxidative stress. At 7 months, _2A/_2C ARKO displayed exercise intolerance and increased muscular noradrenaline, muscular atrophy, capillary rarefaction and increased oxidative stress. ET reestablished _2A/_2C ARKO exercise tolerance to 7 month-old WT levels, and it 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 _2A/_2C ARKO, which highlights its importance as a therapeutic tool for HF.