Insulin Suppresses Atrophy- and Autophagy-related Genes in Heart Tissue and Cardiomyocytes Through AKT/FOXO Signaling

Insulin is an important regulator of the ubiquitin-proteasome system (UPS) and of lysosomal proteolysis in cardiac muscle. However, the role of insulin in the regulation of the muscle atrophy-related Ub-ligases atrogin-1 and MuRF1 as well as in autophagy, a major adaptive response to nutritional stress, in the heart has not been characterized. We report here that acute insulin deficiency in the cardiac muscle of rats induced by streptozotocin increased the expression of atrogin-1 and MuRF1 as well as LC3 and Gabarapl1, 2 autophagy-related genes. These effects were associated with decreased phosphorylation levels of Akt and its downstream target Foxo3a; this phenomenon is a well-known effect that permits the maintenance of Foxo in the nucleus to activate protein degradation by proteasomal and autophagic processes. The administration of insulin increased Akt and Foxo3a phosphorylation and suppressed the diabetes-induced expression of Ub-ligases and autophagy-related genes. In cultured neonatal rat cardiomyocytes, nutritional stress induced by serum/glucose deprivation strongly increased the expression of Ub-ligases and autophagy-related genes; this effect was inhibited by insulin. Furthermore, the addition of insulin in vitro prevented the decrease in Akt/Foxo signaling induced by nutritional stress. These findings demonstrate that insulin suppresses atrophy- and autophagy-related genes in heart tissue and cardiomyocytes, most likely through the phosphorylation of Akt and the inactivation of Foxo3a. © Georg Thieme Verlag KG.

Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Background: Although skeletal muscle atrophy and changes in myosin heavy chain (MyHC) isoforms have often been observed during heart failure, their pathophysiological mechanisms are not completely defined. In this study we tested the hypothesis that skeletal muscle phenotype changes are related to myogenic regulatory factors and myostatin/follistatin expression in spontaneously hypertensive rats (SHR) with heart failure. Methods: After developing tachypnea, SHR were subjected to transthoracic echocardiogram. Pathological evidence of heart failure was assessed during euthanasia. Age-matched Wistar-Kyoto (WKY) rats were used as controls. Soleus muscle morphometry was analyzed in histological sections, and MyHC isoforms evaluated by electrophoresis. Protein levels were assessed by Western blotting. Statistical analysis: Student's t test and Pearson correlation. Results: All SHR presented right ventricular hypertrophy and seven had pleuropericardial effusion. Echocardiographic evaluation showed dilation in the left chambers and left ventricular hypertrophy with systolic and diastolic dysfunction in SHR. Soleus weight and fiber cross sectional areas were lower (WKY 3615±412; SHR 2035±224 μm2; P < 0.001), and collagen fractional volume was higher in SHR. The relative amount of type I MyHC isoform was increased in SHR. Myogenin, myostatin, and follistatin expression was lower and MRF4 levels higher in SHR. Myogenin and follistatin expression positively correlated with fiber cross sectional areas and MRF4 levels positively correlated with I MyHC isoform. Conclusion: 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. © 2012 Elsevier B.V.

Age Affects Exercise-Induced Improvements in Heart Rate Response to Exercise

The aim of the present study was to analyze the effects of age on cardiorespiratory fitness (CRF), muscle strength and heart rate (HR) response to exercise adaptation in women in response to a long-term twice-weekly combined aerobic and resistance exercise program. 85 sedentary women, divided into young (YG; n=22, 30.3±6.2 years), early middle-aged (EMG; n=28, 44.1±2.5 years), late middle-aged (LMG; n=20, 56.7±3.5 years) and older (OG; n=15, 71.4±6.9 years) groups, had their CRF, muscle strength (1-repetition maximum test) and HR response to exercise (graded exercise test) measured before and after 12 months of combined exercise training. Exercise training improved CRF and muscle strength in all age groups (P<0.05), and no significant differences were observed between groups. Exercise training also improved resting HR and recovery HR in YG and EMG (P<0.05), but not in LMG and OG. Maximal HR did not change in any group. Combined aerobic and resistance training at a frequency of 2 days/week improves CRF and muscle strength throughout the lifespan. However, exercise-induced improvements in the HR recovery response to exercise may be impaired in late middle-aged and older women. © Georg Thieme Verlag KG.

The influence of resistance exercise with emphasis on specific contractions (concentric vs. eccentric) on muscle strength and post-exercise autonomic modulation: a randomized clinical trial

Contextualização:Ações concêntricas apresentam maior estresse cardiovascular quando comparadas às excêntricas. Entretanto, não se sabe a influência desses tipos de ações no comportamento da modulação autonômica cardíaca durante o processo de recuperação pós-esforço.Objetivo:Comparar o efeito de um treinamento resistido para o grupo extensor do joelho realizado com ênfase concêntrica vs excêntrica sobre a força muscular e a recuperação pós-exercício considerando índices de variabilidade de frequência cardíaca (VFC) em jovens saudáveis.Método:Cento e cinco homens, com idades entre 18 e 30 anos, foram randomizados em quatro grupos: controle concêntrico (CCONC), controle excêntrico (CEXC), treinamento concêntrico (TCONC) e treinamento excêntrico (TEXC). Os grupos CCONC e CEXC realizaram uma sessão de exercício reduzido (ER) para o grupo extensor do joelho [três séries de uma repetição a 100% de uma repetição máxima (1RM)], e os grupos TCONC e TEXC realizaram dez sessões de treinamento. A VFC foi analisada no momento basal e na recuperação após as sessões (T1, T2, T3 e T4).Resultados:Observou-se aumento da força muscular para o grupo TEXC. Em relação à modulação autonômica cardíaca, observou-se, em comparação ao momento basal, aumento dos índices SDNN e SD2 no momento T1 nos grupos CCONC e CEXC e aumento dos índices RMSSD, SD1 e AF (ms2) nos momentos T1, T2 e T4 no grupo TEXC.Conclusões:Conclui-se que o treinamento resistido realizado com ênfase em contrações excêntricas promoveu ganho de força e aumento da modulação vagal cardíaca durante o processo de recuperação em relação à condição basal.

Adaptive morphology of the heart of Southern-Fur-Seal (Arctocephalus australis - Zimmermamm, 1783)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Heart Failure-Induced Diaphragm Myopathy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Cardiomyopathy and cell therapy: ejection fraction improvement and cardiac muscle mass increasing, after a year of bone marrow stem cells transplantation, by magnetic resonance image

The idiopathic dilated cardiomyopathy (IDC) is one of the major public health problems in the western world. Patients with IDC in functional class IV (New York Health Association - NYHA), even after therapeutic optimization, have high mortality. Stem cell therapy has emerged as a potential therapeutic option for cell death-related heart diseases and several positive effects were assigned to cell therapy in cardiomyopathy. The aim of this study was identify short-term result of cell transplantation in idiopathic dilated cardiomyopathy patients (IDC) who were treated by transplantation of autologous bone marrow mononuclear cells (BMMC). Intracoronary injections of autologous BMMC were performed in eight patients with severe ventricle dysfunction (mean of left ventricle ejection fraction – LEVF=20.03%), cardiac mass muscle around 156.2 g and NYHA between III and IV grades, other 8 IDC patients received placebo. The IDCs were followed - up for one and two years, by magnetic resonance imaging (MRI). The results after one year showed significant improvement in LVEF (mean=181.4) and muscle mass increasing (mean=181.4 g), after two years the LVEF continued improving, reaching a mean of 32.69% and the cardiac muscle mass kept stable (mean=179.4 g). Excepted for one patient, all the other had improvement in the NYHA functional class. The placebo group did not show any improvement. We believe that BMMC implant may be a beneficial therapeutic option for IDC patients.

Long-term low intensity physical exercise attenuates heart failure development in aging spontaneously hypertensive rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Acute effects of flexible pole exercise on heart rate dynamics

Introduction: Exercise with flexible poles provides fast eccentric and concentric muscle contractions. Although the literature reports significant muscle chain activity during this exercise, it is not clear if a single bout of exercise induces cardiac changes. In this study we assessed the acute effects of flexible pole exercise on cardiac autonomic regulation.Methods: The study was performed on 22 women between 18 and 26 years old. We assessed heart rate variability (HRV) in the time (SDNN, RMSSD and pNN50) and frequency (HF, LF and LF/HF ratio) domains and geometric indices of HRV (RRTri, TINN, SD1, SD2 and SD1/SD2 ratio). The subjects remained at rest for 10 min and then performed the exercises with the flexible poles. Immediately after the exercise protocol, the volunteers remained seated at rest for 60 min and HRV was analyzed.Results: We observed no significant changes in time domain (SDNN: p=0.72; RMSSD: p=0.94 and pNN50: p=0.92) or frequency domain indices (LF [nu]: p=0.98; LF [ms(2)]: p=0.72; HF [nu]: p=0.98; HF [ms(2)]: p=0.82 and LF/HF ratio: p=0.7) or in geometric indices (RRTri: p=0.54; TINN: p=0.77; SD1 p=0.94; SD2: p=0.67 and SD/SD2: p=0.42) before and after a single bout of flexible pole exercise.Conclusion: A single bout of flexible pole exercise did not induce significant changes in cardiac autonomic regulation in healthy women. (C) 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

Can geometric indices of heart rate variability predict improvement in autonomic modulation after resistance training in chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is associated with autonomic dysfunctions that can be evaluated through heart rate variability (HRV). Resistance training promotes improvement in autonomic modulation; however, studies that evaluate this scenario using geometric indices, which include nonlinear evaluation, thus providing more accurate information for physiological interpretation of HRV, are unknown. This study aimed to investigate the influence of resistance training on autonomic modulation, using geometric indices of HRV, and peripheral muscle strength in individuals with COPD. Fourteen volunteers with COPD were submitted to resistance training consisting of 24 sessions lasting 60 min each, with a frequency of three times a week. The intensity was determined as 60% of one maximum repetition and was progressively increased until 80% for the upper and lower limbs. The HRV and dynamometry were performed at two moments, the beginning and the end of the experimental protocol. Significant increases were observed in the RRtri (4·81 ± 1·60 versus 6·55 ± 2·69, P = 0·033), TINN (65·36 ± 35·49 versus 101·07 ± 63·34, P = 0·028), SD1 (7·48 ± 3·17 versus 11·04 ± 6·45, P = 0·038) and SD2 (22·30 ± 8·56 versus 32·92 ± 18·78, P = 0·022) indices after the resistance training. Visual analysis of the Poincare plot demonstrated greater dispersion beat-to-beat and in the long-term interval between consecutive heart beats. Regarding muscle strength, there was a significant increase in the shoulder abduction and knee flexion. In conclusion, geometric indices of HRV can predict improvement in autonomic modulation after resistance training in individuals with COPD; improvement in peripheral muscle strength in patients with COPD was also observed.

Hemodynamic response in one session of strength exercise with and without electrostimulation in heart failure patients: a randomized controlled trial

Background: Studies have investigated the influence of neuromuscular electrostimulation on the exercise/muscle capacity of patients with heart failure (HF), but the hemodynamic overload has never been investigated. The aim of our study was to evaluate the heart rate (HR), systolic and diastolic blood pressures in one session of strength exercises with and without neuromuscular electrostimulation (quadriceps) in HF patients and in healthy subjects. Methods: Ten (50% male) HF patients and healthy subjects performed three sets of eight repetitions with and without neuromuscular electrostimulation randomly, with one week between sessions. Throughout, electromyography was performed to guarantee the electrostimulation was effective. The hemodynamic variables were measured at rest, again immediately after the end of each set of exercises, and during the recovery period. Results: Systolic and diastolic blood pressures did not change during each set of exercises among either the HF patients or the controls. Without electrostimulation: among the controls, the HR corresponding to the first (85 ± 13 bpm, p = 0.002), second (84 ± 10 bpm, p < 0.001), third (89 ± 17, p < 0.001) sets and recuperation (83 ± 16 bpm, p = 0.012) were different compared to the resting HR (77 bpm). Moreover, the recuperation was different to the third set (0.018). Among HF patients, the HR corresponding to the first (84 ± 9 bpm, p = 0.041) and third (84 ± 10 bpm, p = 0.036) sets were different compared to the resting HR (80 ± 7 bpm), but this increase of 4 bpm is clinically irrelevant to HF. With electrostimulation: among the controls, the HR corresponding to the third set (84 ± 9 bpm) was different compared to the resting HR (80 ± 7 bmp, p = 0.016). Among HF patients, there were no statistical differences between the sets. The procedure was well tolerated and no subjects reported muscle pain after 24 hours. Conclusions: One session of strength exercises with and without neuromuscular electrostimulation does not promote a hemodynamic overload in HF patients. (Cardiol J 2011; 18, 1: 39-46)

T-cell lymphoma in the tongue of a dog with cutaneous and striated forelimb muscle involvement

Background: Primary tongue tumors rarely affect dogs and correspond to 4% of tumors involving the oropharynx. Until now, primary tongue lymphoma had not been reported. However, lymphoma involvement in the skeletal muscle, although quite unusual, was described in the literature in four cases. Cutaneous lymphoma is another rare extranodal manifestation. The objective of this report is to describe a case of T immunophenotype lymphoma occurrence, whose manifestation is atypical, not only because it is situated in the tongue muscle but also because of the subsequent involvement of the striated musculature of the left forelimb and the skin, which showed unfavorable evolution. Case: A female seven-year-old mongrel was seen showing a regular lump in the base of the tongue, 3 cm in diameter, not ulcerated and of fi rm consistency, with halitosis as the only clinical sign of the disease. Incisional biopsy of the lump was performed and histopathology verifi ed that it was large cell lymphoma. The material was sent for immunohistochemical evaluation and was characterized as T immunophenotype lymphoma by positive CD3 and negative CD79a marking. The CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy protocol was established as treatment and after the fi rst chemotherapy session there was partial remission of the mass, measuring 2 cm in diameter. The lump, however, remained stable in the following sessions. Thirty days after the diagnosis of lymphoma, the animal began to show lameness of the left forelimb and swelling near the head of the left humerus. A muscle mass, fi rm in consistency, progressing fast, presented a signifi cant increase, just three weeks after its appearance. Two skin lesions, arcuate, erythematous and pruritic also appeared in the dorsocervical and ventral-abdominal region. Incisional biopsy of these lesions was performed and the histopathological diagnosis confi rmed muscle and cutaneous large cell lymphoma and immunophenotype compatible with T cells (positive CD3 and negative CD79a). Due to disease advance, even during chemotherapy, a rescue protocol of L-asparaginase administration followed by lomustine and prednisone was proposed. Even with the rescue protocol there was no remission of the tumors and the case was classifi ed as progressive. The animal of this report died after completing the fi rst cycle of chemotherapy protocol, with a survival of 92 days. Discussion: Despite the fact that clinical behavior of primary lymphoma in dogs’ skeletal muscle is unknown, it is believed that, as in humans, it can be associated with chronic infl ammation or neoplastic cell invasion by proximity of the tumor or metastasis, which could justify the dissemination of the lymphoma reported here from the tongue to other tissues. However, appearance of concurrent independent lymphomas cannot be ruled out. As observed in the three cases of primary muscular lymphoma, the dog of this report had low response to therapy and short survival. This report presents the fi rst case of lymphoma in tongue with subsequent skin and left forelimb skeletal muscle involvement described in the literature. The clinical outcome corroborates the aggressiveness of muscular lymphoma observed in the other reports and also suggests that both tongue and other skeletal muscle tumors should be included in the differential diagnosis of canine lymphoma.