Ramires PR, Moriscot AS, Brum PC. Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training. J Appl Physiol 106: 1631-1640, 2009. First published January 29, 2009 doi:10.1152/japplphysiol.91067.2008.-Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HFinduced 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 3 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 HEART FAILURE (HF) is a clinical syndrome with poor prognosis characterized by exercise intolerance, early fatigue, and skeletal muscle myopathy associated with atrophy and shift toward fast-twitch fibers (27,28,49). The development of end-stage HF often involves a myocardial insult that reduces cardiac output, which leads to a compensatory increase in sympathetic nervous activity (4, 5). Although beneficial acutely, chronic increase of sympathetic activity leads to further pathological changes in the heart with a progressive deterioration of cardiac function (7,24,38,39), which is closely related to increased cardiac oxidative stress (52).Several lines of evidence suggest that sympathetic hyperactivity also contributes to the skeletal myopathy of HF, since it leads to chronic vasoconstriction in HF patients (22,35,44) associated with skeletal muscle oxidative stress (34,46,53) and increased concentrations of proinflammatory cytokines (12, 23). However, little is known ...
Reactive oxygen species and other oxidants are implicated in the mechanisms of biological ageing and exercise-induced tissue damage. The present study examined the effects of ageing and an acute bout of exercise on intracellular oxidant generation, lipid peroxidation, protein oxidation and glutathione (GSH) status in the heart and liver of young adult (8 month, N=24) and old (24 month, N=24) male Fischer 344 rats. Young rats ran on treadmill at 25 m min-1, 5% grade until exhaustion (55.4+/-2.7 min), whereas old rats ran at 15 m min-1, 5% until exhaustion (58.0+/-2.7 min). Rate of dichlorofluorescin (DCFH) oxidation, an indication of intracellular oxidant production, was significantly higher in the homogenates of aged heart and liver compared with their young counterparts. In the isolated heart and liver mitochondria, ageing increased oxidant production by 29 and 32% (P<0.05), respectively. Acute exercise increased oxidant production in the aged heart but not in the liver. When nicodinamide dinucleotide phosphate (reduced), adenosine diphosphate and Fe3+ were included in the assay, DCFH oxidation rate was 47 and 34% higher (P<0.05) in the aged heart and liver homogenates, respectively, than the young ones. The age differences in the induced state reached 83 and 140% (P<0.01) in isolated heart and liver mitochondria, respectively. Lipid peroxidation was increased in the aged liver and exercised aged heart, whereas protein carbonyl content was elevated only in the aged heart (P<0.05). Although our data using DCFH method probably underestimated cellular oxidant production because of time delay and antioxidant competition, it is clear that oxidative stress was enhanced in both heart and liver with old age. Furthermore, aged myocardium showed greater susceptibility to oxidative stress after heavy exercise.
The present study examined the effects of oral reduced glutathione (GSH) supplementation in conjunction with endurance training on contractile function, antioxidant defense, and oxidative damage in response to ischemia-reperfusion (I/R) in rat hearts. Female Sprague-Dawley rats (age 4 mo, n = 72) were randomly assigned to a treadmill-trained (T; 25 m/min, 15% grade, for 75 min/day, 5 days/wk, for 10 wk) or untrained (U) group. Each group was further divided into rats receiving 5 g GSH/kg diet during the final 17 days of training (GSH-S) and control (C) groups. One-half of each group of rats was subjected to I/R by surgical occlusion of the main coronary artery for 45 min, followed by 30-min reperfusion or sham operation. Left ventriclar (LV) peak systolic pressure (LVSP) and contractility (+dP/dt), measured with a catheter inserted into the LV via the carotid artery, decreased with I/R in all groups (P < 0.05). However, LVSP with I/R in the T/GSH-S group was 9.5%, 17%, and 18% higher (P < 0.05) than that in the U/GSH-S, T/C, and U/C groups, respectively. +dP/dt with I/R was 19%, 27%, and 29% (P < 0.05) greater in the T/GSH-S group versus the T/C, U/GSH-S, and U/C groups, respectively. I/R decreased heart GSH content by 12-17% (P < 0.05) and increased oxidized glutathione (GSSG) by 20-27% (P < 0.05). T/GSH-S hearts showed 15% higher GSH (P < 0.05) and a 32% higher GSH-to-GSSG ratio (P < 0.05) than the U/C group at the end of I/R. Myocardial superoxide dismutase, GSH peroxidase, glutathione reductase, and gamma-glutamyl transpeptidase activities were increased with treadmill training in both GSH-S and C rats. I/R induced myocardial lipid peroxidation and lactate dehydrogenase release were attenuated with T/GSH-S treatment. The present data indicate that training in conjunction with dietary GSH supplementation can increase myocardial GSH content and antioxidant defense capacity, thereby protecting the intact heart against oxidative damage and functional retardation caused by I/R.
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