Skeletal muscle abnormalities are responsible for significant disability in the elderly. Sarcopenia is the main alteration occurring during senescence and a key public health issue as it predicts frailty, poor quality of life, and mortality. Several factors such as reduced physical activity, hormonal changes, insulin resistance, genetic susceptibility, appetite loss, and nutritional deficiencies are involved in the physiopathology of muscle changes. Sarcopenia is characterized by structural, biochemical, molecular and functional muscle changes. An imbalance between anabolic and catabolic intracellular signaling pathways and an increase in oxidative stress both play important roles in muscle abnormalities. Currently, despite the discovery of new targets and development of new drugs, nonpharmacological therapies such as physical exercise and nutritional support are considered the basis for prevention and treatment of age-associated muscle abnormalities. There has been an increase in information on signaling pathways beneficially modulated by exercise; nonetheless, studies are needed to establish the best type, intensity, and frequency of exercise to prevent or treat age-induced skeletal muscle alterations.

Background: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). Methods: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. Statistical analyses: ANOVA and Tukey or Mann-Whitney, and Goodman test. Results: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR-SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR-SED than WKY-SED. Conclusion: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis.

Objective. We evaluated the influence of exercise on functional capacity, cardiac remodeling, and skeletal muscle oxidative stress, MAPK, and NF-κB pathway in rats with aortic stenosis- (AS-) induced heart failure (HF). Methods and Results. Eighteen weeks after AS induction, rats were assigned into sedentary control (C-Sed), exercised control (C-Ex), sedentary AS (AS-Sed), and exercised AS (AS-Ex) groups. Exercise was performed on treadmill for eight weeks. Statistical analyses were performed with Goodman and ANOVA or Mann-Whitney. HF features frequency and mortality did not differ between AS groups. Exercise improved functional capacity, assessed by maximal exercise test on treadmill, without changing echocardiographic parameters. Soleus cross-sectional areas did not differ between groups. Lipid hydroperoxide concentration was higher in AS-Sed than C-Sed and AS-Ex. Activity of antioxidant enzymes superoxide dismutase and glutathione peroxidase was changed in AS-Sed and restored in AS-Ex. NADPH oxidase activity and gene expression of its subunits did not differ between AS groups. Total ROS generation was lower in AS-Ex than C-Ex. Exercise modulated MAPK in AS-Ex and did not change NF-κB pathway proteins. Conclusion. Exercise improves functional capacity in rats with AS-induced HF regardless of echocardiographic parameter changes. In soleus, exercise reduces oxidative stress, preserves antioxidant enzyme activity, and modulates MAPK expression.

Reduced myogenin and follistatin expression seems to participate in muscle atrophy while increased MRF4 protein levels can modulate myosin heavy chain isoform shift in skeletal muscle of spontaneously hypertensive rats with heart failure.

Background: Intracellular signaling pathways involved in skeletal myosin heavy chain (MyHC) isoform alterations during heart failure (HF) are not completely understood. We tested the hypothesis that diaphragm expression of mitogen-activated protein kinases (MAPK) and myogenic regulatory factors is changed in rats with myocardial infarction (MI) induced HF. Methods: Six months after MI rats were subjected to transthoracic echocardiography. After euthanasia, infarcted rats were subdivided in MI/HF- group (with no HF evidence; n=10), and MI/HF+ (with right ventricular hypertrophy and lung congestion; n=10). Sham-operated rats were used as controls (n=10). MyHC isoforms were analyzed by electrophoresis. Statistical analysis: ANOVA and Pearson correlation. Results: MI/HF- had left cardiac chambers dilation with systolic and diastolic left ventricular dysfunction. Cardiac injury was more intense in MI/HF+ than MI/HF-. MyHC I isoform percentage was higher in MI/HF+ than MI/HF-, and IIb isoform lower in MI/HF+ than Sham. Left atrial diameter-to-body weight ratio positively correlated with MyHC I (p=0.005) and negatively correlated with MyHC IIb (p=0.02). TNF-a serum concentration positively correlated with MyHC I isoform. Total and phosphorylated ERK was lower in MI/HF- and MI/HF+ than Sham. Phosphorylated JNK was lower in MI/HF- than Sham. JNK and p38 did not differ between groups. Expression of NF-κB and the myogenic regulatory factors MyoD, myogenin, and MRF4 was similar between groups. Conclusion: Diaphragm MyHC fast-to-slow shift is related to cardiac dysfunction severity and TNF-a serum levels in infarcted rats. Reduced ERK expression seems to participate in MyHC isoform changes. Myogenic regulatory factors and NF-κB do not modulate diaphragm MyHC distribution during chronic HF.

Background: The role of aldosterone blockers during transition from long-term compensated hypertrophy to dilated failure is not completely understood. In this study we evaluated the effects of early administration of spironolactone on cardiac remodeling, myocardial function, and mortality in spontaneously hypertensive rats (SHR). Methods: Sixteen-month-old SHR received no treatment (SHR-C, n=72) or spironolactone (SHR-SPR, 20 mg/kg/day, n=34) for six months. Echocardiogram was performed before and after treatment. Myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Myocardial collagen and hydroxyproline concentration were evaluated by morphometry and spectrophotometry, respectively. LV gene expression was assessed by real time RT-PCR. Statistics: Student's t test; Log rank test (Kaplan Meyer). Results: SHR-C and SHR-SPR presented mortality rates of 71 and 38%, respectively (p=0.004). Systolic arterial pressure did not differ between groups (SHR-C 199±43; SHR-SPR 200±35 mmHg). Initial and final echocardiograms did not show significant differences in cardiac structures or LV function between groups. Myocardial function was similar between groups at basal and after inotropic stimulation. Collagen fractional area, hydroxyproline concentration, gene expression for α- and β-myosin heavy chain, atrial natriuretic peptide, and Serca2a were not different between groups. Conclusion: Early spironolactone administration reduces mortality without changing cardiac remodeling in spontaneous hypertensive rats.

Background: Chronic heart failure is characterized by decreased exercise capacity with early exacerbation of fatigue and dyspnea. Intrinsic skeletal muscle abnormalities can play a role in exercise intolerance. Causal or contributing factors responsible for muscle alterations have not been completely defined. This study evaluated skeletal muscle oxidative stress and NADPH oxidase activity in rats with myocardial infarction (MI) induced heart failure. Methods and Results: Four months after MI, rats were assigned to Sham, MI-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. In soleus muscle, glutathione peroxidase and superoxide dismutase activity was decreased in MI-C and unchanged by NAC. 3-nitrotyrosine was similar in MI-C and Sham, and lower in MI-NAC than MI-C. Total reactive oxygen species (ROS) production was assessed by HPLC analysis of dihydroethidium (DHE) oxidation fluorescent products. The 2-hydroxyethidium (EOH)/DHE ratio did not differ between Sham and MI-C and was higher in MI-NAC. The ethidium/DHE ratio was higher in MI-C than Sham and unchanged by NAC. NADPH oxidase activity was similar in Sham and MI-C and lower in MI-NAC. Gene expression of p47^phox was lower in MI-C than Sham. NAC decreased NOX4 and p22^phox expression. Conclusions: We corroborate the case that oxidative stress is increased in skeletal muscle of heart failure rats and show for the first time that oxidative stress is not related to increased NADPH oxidase activity.

Late exercise improves systolic function and modulates intracellular calcium signaling proteins in rats with moderate and large MI.