Modulation of MAPK and NF-954;B Signaling Pathways by Antioxidant Therapy in Skeletal Muscle of Heart Failure Rats.

BACKGROUND/AIMS: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats. METHODS AND RESULTS: Four months after surgery, rats were assigned to Sham, myocardial infarction (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. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 ± 0.056; MI-C 0.223 ± 0.073; MI-NAC 0.136 ± 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-954;B p65 subunit was reduced; p-Ser276 in p65 and I954;B was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-954;B p65 subunit, but decreased p-Ser276 and p-Ser536. CONCLUSION: N-acetylcysteine modulates MAPK and NF-954;B signaling pathways in soleus muscle of HF rats.

Influence of N- acetylcysteine on oxidative stress in slow-twitch soleus muscle of heart failure 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.

Heart failure-induced diaphragm myopathy.

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-α 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-α 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.

Aldosterone is not involved in the ventricular remodeling process induced by tobacco smoke exposure.

BACKGROUND/AIMS: Renin-angiotensin-aldosterone system blockade with a mineralocorticoid-receptor antagonist has not yet been studied in exposure to tobacco smoke (TS) models. Thus, this study investigated the role of spironolactone on cardiac remodeling induced by exposure to tobacco smoke. METHODS: Male Wistar rats were divided into 4 groups: a control group (group C, n=11); a group with 2 months of cigarette smoke exposure (group TS-C, n=13); a group that received spironolactone 20 mg/kg of diet/day and no cigarette smoke exposure (group TS-S, n=13); and a group with 2 months of cigarette smoke exposure and spironolactone supplementation (group S, n=12). The rats were observed for a period of 60 days, during which morphological, biochemical and functional analyses were performed. RESULTS: There was no difference in invasive mean arterial pressure among the groups. There were no interactions between tobacco smoke exposure and spironolactone in the morphological and functional analysis. However, in the echocardiographic analysis, the TS groups had left chamber enlargement, higher left ventricular mass index and higher isovolumetric relaxation time corrected by heart rate compared with the non-TS groups. In vitro left ventricular diastolic function also worsened in the TS groups and was not influenced by spironolactone. In addition, there were no differences in myocardial levels of IFN-γ, TNF-α, IL-10, ICAM-1 and GLUT4 [TS: OR 0.52, 95%CI (-0.007; 0.11); Spironolactone: OR -0.01, 95%CI (-0.07;0.05)]. CONCLUSION: Our data do not support the participation of aldosterone in the ventricular remodeling process induced by exposed to cigarette smoke.

Miostatina e redução da massa muscular em doenças crônicas / Myostatin and muscle mass in chronic diseases

JUSTIFICATIVA E OBJETIVOS: A miostatina, também conhecida como fator de crescimento e diferenciação-8 (GDF-8), regula o crescimento de músculos esqueléticos durante o desenvolvimento embrionário e na vida adulta. Foi descoberta em pesquisas para identificar novos membros da superfamília fator transformador do crescimento-Beta (TGF-Beta) de fatores de diferenciação e crescimento celular. Os objetivos deste estudo consistiram em descrever o histórico e as características da miostatina, resumo de estudos sobre mecanismo de ação em condições fisiológicas e patológicas, por meio de estudos em humanos e modelos experimentais em animais, bem como as perspectivas futuras de utilização terapêutica de antagonistas da miostatina. CONTEÚDO: Estudos sobre os efeitos da miostatina mostraram correlação negativa entre sua expressão e massa muscular, sugerindo que possa estar envolvida na indução de hipotrofia e inibição do crescimento da musculatura esquelética. O mecanismo de ação da miostatina também foi avaliado, experimentalmente, em várias doenças como insuficiência cardíaca, neoplasias, cirrose, distrofias musculares, uremia e denervação. Os resultados sugerem que amiostatina exerce ações relevantes na redução da musculatura esquelética associada a estas condições. Também em humanos, os estudos realizados com indivíduos saudáveis e em pacientes com doenças crônicas reforçam este conceito. Entre as perspectivas para o futuro, ainda em fase de investigação experimental, há possibilidades terapêuticas que permitam antagonizar a ação da miostatina e reverter ou impedir a perda de massa muscular associada a doenças crônicas. Entre elas incluem-se anticorpos monoclonais anti-miostatina, propeptídeo da miostatina resistente à clivagem, forma solúvel do receptor activina tipo IIB e folistatina...

BACKGROUND AND OBJECTIVES: Myostatin, or GDF-8 (growth and differentiation factor-8), regulates muscle growth during development and adult life. Myostatin was originally identified in a screen for novel members of the transforming growth factor-Beta (TGF-Beta) superfamily of growth and differentiation factors. In this short review we describe myostatin characteristics, summary of studies on myostatin during physiological and pathological settings in human and experimental animal?s studies and future directions on myostatin antagonism.CONTENTS: Studies about the myostatin effects have shown a negative correlation between myostatin expression and muscle mass suggesting its involvement on muscle growth inhibition and atrophy. Myostatin has also been experimentally evaluated in several diseases such as heart failure, cancer, cirrhosis, muscular dystrophy, uremia, and denervation. The results suggest that myostatin can play an important role on chronic disease-associated skeletal muscle wasting. Although human studies are sparse, evaluation performed in healthy individuals and chronically diseased patients reinforces this hypothesis. Considering future perspectives, there is therapeutic potential to inhibit myostatin activity and treat or prevent muscle loss associated with chronic diseases. This includes myostatin neutralizing antibodies, protease resistant form of the myostatin propeptide, soluble version of the activin RIIB receptor, and follistatin. CONCLUSION: Experimental studies validate myostatin inhibition as a therapeutic approach to muscular dystrophy and chronic disease-associated muscle wasting.