No abstract

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 ...

Moreira JB, Bechara LR, Bozi LH, Jannig PR, Monteiro AW, Dourado PM, Wisløff U, Brum PC. High-versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J Appl Physiol 114: 1029 -1041, 2013. First published February 21, 2013 doi:10.1152/japplphysiol.00760.2012.-Poor skeletal muscle performance was shown to strongly predict mortality and long-term prognosis in a variety of diseases, including heart failure (HF). Despite the known benefits of aerobic exercise training (AET) in improving the skeletal muscle phenotype in HF, the optimal exercise intensity to elicit maximal outcomes is still under debate. Therefore, the aim of the present study was to compare the effects of highintensity AET with those of a moderate-intensity protocol on skeletal muscle of infarcted rats. Wistar rats underwent myocardial infarction (MI) or sham surgery. MI groups were submitted either to an untrained (MI-UNT); moderate-intensity (MI-CMT, 60% V O2 max); or matched volume, high-intensity AET (MI-HIT, intervals at 85% V O2 max) protocol. High-intensity AET (HIT) was superior to moderate-intensity AET (CMT) in improving aerobic capacity, assessed by treadmill running tests. Cardiac contractile function, measured by echocardiography, was equally improved by both AET protocols. CMT and HIT prevented the MI-induced decay of skeletal muscle citrate synthase and hexokinase maximal activities, and increased glycogen content, without significant differences between protocols. Similar improvements in skeletal muscle redox balance and deactivation of the ubiquitin-proteasome system were also observed after CMT and HIT. Such intracellular findings were accompanied by prevented skeletal muscle atrophy in both MI-CMT and MI-HIT groups, whereas no major differences were observed between protocols. Taken together, our data suggest that despite superior effects of HIT in improving functional capacity, skeletal muscle adaptations were remarkably similar among protocols, leading to the conclusion that skeletal myopathy in infarcted rats was equally prevented by either moderate-intensity or high-intensity AET. atrophy; heart failure; proteasome; oxidative stress SKELETAL MUSCLE ABNORMALITIES in systemic diseases have been described for decades (9, 14, 29, 52), including in heart failure (HF). Capillary rarefaction, switch from type I (oxidative) to type II (glycolytic) fibers, impaired metabolism, and skeletal muscle atrophy have been shown in human and experimental models of HF (14,21,29,43,49,52). This maladaptation seems to impair skeletal muscle performance, which was proposed as the main determinant of exercise capacity in patients with HF (21,32,40). Additionally, skeletal muscle loss was shown to be an independent predictor of mortality in HF (3).Recent efforts by researchers have identified possible intracellular mechanisms underlying the skeletal muscle abnormalities in cardiovascular diseases, and promising targets such as metabolic enzymes, calcium handling-related proteins, antioxidant scavengers, and in...

We previously reported that facilitating the clearance of damaged mitochondria through macroautophagy/autophagy protects against acute myocardial infarction. Here we characterize the impact of exercise, a safe strategy against cardiovascular disease, on cardiac autophagy and its contribution to mitochondrial quality control, bioenergetics and oxidative damage in a post-myocardial infarction-induced heart failure animal model. We found that failing hearts displayed reduced autophagic flux depicted by accumulation of autophagy-related markers and loss of responsiveness to chloroquine treatment at 4 and 12 wk after myocardial infarction. These changes were accompanied by accumulation of fragmented mitochondria with reduced O consumption, elevated HO release and increased Ca-induced mitochondrial permeability transition pore opening. Of interest, disruption of autophagic flux was sufficient to decrease cardiac mitochondrial function in sham-treated animals and increase cardiomyocyte toxicity upon mitochondrial stress. Importantly, 8 wk of exercise training, starting 4 wk after myocardial infarction at a time when autophagy and mitochondrial oxidative capacity were already impaired, improved cardiac autophagic flux. These changes were followed by reduced mitochondrial number:size ratio, increased mitochondrial bioenergetics and better cardiac function. Moreover, exercise training increased cardiac mitochondrial number, size and oxidative capacity without affecting autophagic flux in sham-treated animals. Further supporting an autophagy mechanism for exercise-induced improvements of mitochondrial bioenergetics in heart failure, acute in vivo inhibition of autophagic flux was sufficient to mitigate the increased mitochondrial oxidative capacity triggered by exercise in failing hearts. Collectively, our findings uncover the potential contribution of exercise in restoring cardiac autophagy flux in heart failure, which is associated with better mitochondrial quality control, bioenergetics and cardiac function.

Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients.