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

¹School of Physical Education and Sport, ²Department of Physiology and Biophysics, Biomedical Sciences Institute, and ³Heart Institute (InCor), Medical School, University of Sao Paulo, Sao Paulo; ⁴Department of Medicine, Division of Nephrology, Federal University of Sao Paulo, Sao Paulo; and ⁵Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, Brazil

Submitted 7 August 2008 ; accepted in final form 28 January 2009

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- and _2C-adrenergic receptor subtypes (_2A/_2CARKO 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, _2A/_2CARKO mice were exercised from 5 to 7 mo of age. At 3 mo, _2A/_2CARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of _2A/_2CARKO mice displayed hypertrophy and fiber type shift (IIA IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, _2A/_2CARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished _2A/_2CARKO 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 _2A/_2CARKO mice, which highlights its importance as a therapeutic tool for HF.

oxidative stress; _2A/_2C-adrenergic receptor knockout mice; cardiac cachexia