Differential regulation of cysteine oxidative post-translational modifications in high and low aerobic capacity.

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.

MicroRNAs as Important Regulators of Exercise Adaptation.

A significant body of evidence supports the protective role of exercise training (ET) in cardiovascular diseases, skeletal muscle dystrophies, several types of cancer, Alzheimer disease or even in the recovery of spinal cord injury. In spite of this, the molecular mechanisms underlying the beneficial effects of exercise training are not well understood and remain elusive. Several mechanisms have been proposed in the past, but more recently microRNAs (miRNAs), small non-coding RNA molecules involved in a variety of basic biological processes that negatively modulate gene expression, recognized as important regulatory molecules. In this review, we highlight recent advances on the miRNA involvement in the benefits of ET. Here, we assess the role of microRNAs expressed in the heart, in the skeletal muscle, detected in the circulation (serum and plasma), and in other conditions (e.g., spinal cord injury). Additionally, the long-term effects of diverse ET modalities (e.g., running, cycling, resistance training) in the cardiac miRNA profile are properly addressed.

Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53.

Here we present the application of our adeno-associated virus (AAV2) vector where transgene expression is driven by a synthetic, p53-responsive promoter, termed PG, used to supply human vascular endothelial growth factor-A165 (VEGF-A). Thus, p53 is harnessed to promote the beneficial expression of VEGF-A encoded by the AAVPG vector, bypassing the negative effect of p53 on HIF-1α which occurs during cardiac hypertrophy. Wistar rats were submitted to pressure overload induced by thoracic aorta coarctation (TAC) with or without concomitant gene therapy (intramuscular delivery in the left ventricle). After 12 weeks, rats receiving AAVPG-VEGF gene therapy were compared to those that did not, revealing significantly improved cardiac function under hemodynamic stress, lack of fibrosis and reversal of capillary rarefaction. With these functional assays, we have demonstrated that application of the AAVPG-VEGF vector under physiologic conditions known to stimulate p53 resulted in the preservation of cardiac performance.

Reversible pulmonary trunk banding VIII: Intermittent overload causes harmless hypertrophy in adult goat.

BACKGROUND: Traditional pulmonary artery banding (PAB) is not always suitable for mature subpulmonary ventricle retraining. We sought to assess in detail the myocardial morphologic adaptations of two different protocols for inducing right ventricular (RV) hypertrophy in an adult animal model. METHODS: Eighteen adult goats were distributed into three groups: sham (no systolic overload), traditional (continuous systolic overload), and intermittent (daily 12-hour systolic overload). Systolic overload was adjusted to achieve a 0.7 RV-to-aortic pressure ratio. All animals underwent weekly echocardiographic studies, and hemodynamic evaluations were performed 3 times a week. After 4 weeks, the animals were humanely killed for morphologic assessment. RESULTS: A 37.2% increase was observed in the RV wall thickness of the intermittent group (p<0.05), but no significant echocardiographic changes were observed in the other two groups. The intermittent and traditional groups had a 55.7% and 36.7% increase in RV mass, respectively, compared with the sham group (p<0.05). No differences were observed in myocardial water content of the three groups (p=0.27). RV myocardial fiber and nuclei diameters were increased in the intermittent group compared with the sham group (p<0.05). The area of collagen deposition in the RV interstitium was increased 98% in traditional group compared with the sham group (p<0.05). No significant cellular proliferation occurred in any group. CONCLUSIONS: This study suggests that a more effective and harmless hypertrophy can be achieved in adult animals using intermittent PAB compared with the traditional approach.

Reversible pulmonary trunk banding: VII. Stress echocardiographic assessment of rapid ventricular hypertrophy in young goats.

BACKGROUND: Ventricle retraining with abrupt systolic overload can cause myocardial edema and necrosis, followed by late ventricular failure. Intermittent systolic overload could minimize the inadequacy of conventional pulmonary artery banding. The present study compared ventricle function under dobutamine stress in 2 protocols of systolic overload in young goats. METHODS: Nineteen young goats were divided into 3 groups: sham (n = 7; no systolic pressure overload), continuous (n = 6; systolic overload maintained for 96 hours), and intermittent (n = 6; 4 periods of 12-hour systolic overload, paired with a 12-hour resting period). Echocardiographic and hemodynamic evaluations were performed daily. The myocardial performance index and ejection fraction were evaluated at rest and during dobutamine stress. The goats were then killed for morphologic evaluation. RESULTS: The intermittent group underwent less systolic overload than the continuous group (P < .05). Nevertheless, both groups had increased right ventricular and septal masses compared with the sham group (P < .0002). Echocardiography revealed a major increase in right ventricular wall thickness in the intermittent group (+64.8% ± 23.37%) compared with the continuous group (+43.9% ± 19.26%; P = .015). Only the continuous group remained with significant right ventricular dilation throughout the protocol (P < .001). The intermittent group had a significantly better myocardial performance index at the end of the protocol, under resting and dobutamine infusion, compared with the continuous group (P < .012). CONCLUSIONS: Both systolic overload protocols have induced rapid right ventricular hypertrophy. However, only the intermittent group had better preservation of right ventricular function at the end of the protocol, both at rest and during dobutamine infusion.

Reversible pulmonary trunk banding. VI: Glucose-6-phosphate dehydrogenase activity in rapid ventricular hypertrophy in young goats.

OBJECTIVE: Increased myocardial glucose-6-phosphate dehydrogenase (G6PD) activity occurs in heart failure. This study compared G6PD activity in 2 protocols of right ventricle (RV) systolic overload in young goats. METHODS: Twenty-seven goats were separated into 3 groups: sham (no overload), continuous (continuous systolic overload), and intermittent (four 12-hour periods of systolic overload paired with a 12-hour resting period). During a 96-hour protocol, systolic overload was adjusted to achieve a 0.7 RV/aortic pressure ratio. Echocardiographic and hemodynamic evaluations were performed before and after systolic overload every day postoperatively. After the study period, the animals were humanely killed for morphologic and G6PD tissue activity assessment. RESULTS: A 92.1% and 46.5% increase occurred in RV and septal mass, respectively, in the intermittent group compared with the sham group; continuous systolic overload resulted in a 37.2% increase in septal mass. A worsening RV myocardial performance index occurred in the continuous group at 72 hours and 96 hours, compared with the sham (P < .039) and intermittent groups at the end of the protocol (P < .001). Compared with the sham group, RV G6PD activity was elevated 130.1% in the continuous group (P = .012) and 39.8% in the intermittent group (P = .764). CONCLUSIONS: Continuous systolic overload for ventricle retraining causes RV dysfunction and upregulation of myocardial G6PD activity, which can elevate levels of free radicals by NADPH oxidase, an important mechanism in the pathophysiology of heart failure. Intermittent systolic overload promotes a more efficient RV hypertrophy, with better preservation of myocardial performance and and less exposure to hypertrophic triggers.

Sobrecarga sistólica intermitente promove melhor desempenho miocárdico em animais adultos / Intermittent systolic overload promotes better myocardial performance in adult animals / Sobrecarga sistólica intermitente promueve mejor desempeño miocárdico en animales adultos

FUNDAMENTO: A transposição corrigida das grandes artérias frequentemente evolui com disfunção ventricular direita. O preparo ventricular para a correção anatômica em pacientes adultos apresenta resultados desapontadores. OBJETIVO: Analisar a hipertrofia do ventrículo direito (VD) induzida por dois tipos de bandagem pulmonar (BP), convencional e intermitente em animais adultos. MÉTODOS: Dezenove cabras adultas foram divididas em três grupos: Convencional (seis animais), Intermitente (seis animais) e Controle (sete animais). O grupo Convencional foi submetido à BP fixa com fita cardíaca, enquanto no grupo Intermitente foi usado dispositivo de BP ajustável, que gerava sobrecarga sistólica por 12 horas, alternada com 12 horas de descanso do VD. As pressões de VD, tronco pulmonar e aorta foram medidas durante todo o estudo. Ecocardiograma foi realizado semanalmente. Após quatro semanas, os animais foram eutanasiados para avaliação morfológica dos ventrículos. O grupo Controle foi submetido a eutanásia para análise em condições basais. RESULTADOS: A sobrecarga pressórica foi menor no grupo Intermitente (p=0,001), comparada ao grupo Convencional. Houve aumento na espessura do VD do grupo Intermitente, medida pelo ecocardiograma, comparado ao seu momento basal (p<0,05). O índice de performance miocárdica do VD foi melhor no grupo Intermitente (p=0,024), comparado ao Convencional. Os grupos estimulados apresentaram aumento da massa muscular em comparação ao grupo Controle (p=0,001). Não houve diferença no conteúdo de água miocárdica. CONCLUSÃO: A BP intermitente desenvolveu hipertrofia de melhor desempenho funcional, sugerindo este protocolo como método preferencial de preparo ventricular.

BACKGROUND: Corrected transposition of great arteries often evolves with right ventricular dysfunction. The ventricular preparation for anatomic correction in adult patients has produced disappointing results. OBJECTIVE: To assess right ventricular hypertrophy (RV) induced by conventional and intermittent pulmonary banding (PB) in adult animals. METHODS: Nineteen adult goats were divided into three groups: conventional (six animals), intermittent (six animals) and control (seven animals). The Conventional group underwent fixed PB with cardiac tape, while the intermittent group received PB adjustable device, which generated systolic overload for 12 hours, alternated with 12 hours of rest of RV. The pressures of the RV, pulmonary artery and aorta were measured throughout the study. Echocardiography was performed weekly. After four weeks, the animals were euthanized for morphological evaluation of the ventricles. The Control group was put to euthanasia for analysis at baseline. RESULTS: Pressure overload was lower in the intermittent group (p = 0.001), compared to the conventional group. There was an increase in the thickness of the RV of the Intermittent group measured by echocardiography compared to their baseline values (p < 0.05). The myocardial performance index in the RV group was better in the Intermittent group (p = 0.024), compared to the Conventional group. The groups stimulated showed increased muscle mass compared to the Control group (p = 0.001). There was no difference in myocardial water content. CONCLUSION: The intermittent BP developed hypertrophy of better performance, suggesting this protocol as the preferred method of ventricular preparation.

FUNDAMENTO: La transposición corregida de las grandes arterias frecuentemente evoluciona con disfunción ventricular derecha. La preparación ventricular para la corrección anatómica en pacientes adultos presenta resultados desalentadores. OBJETIVO: Analizar la hipertrofia del ventrículo derecho (VD) inducida por dos tipos de vendaje pulmonar (VP), convencional e intermitente en animales adultos. MÉTODOS: Diecinueve cabras adultas fueron divididas en tres grupos: Convencional (seis animales), Intermitente (seis animales) y Control (siete animales). El grupo Convencional fue sometido al VP fijo con cinta cardíaca, mientras que en el grupo Intermitente fue usado dispositivo de VP ajustable, que generaba sobrecarga sistólica por 12 horas, alternada con 12 horas de descanso del VD. Las presiones de VD, tronco pulmonar y aorta fueron medidas durante todo el estudio. Ecocardiograma fue realizado semanalmente. Después de cuatro semanas, los animales fueron eutanasiados para evaluación morfológica de los ventrículos. El grupo Control fue sometido a eutanasia para análisis en condiciones basales. RESULTADOS: La sobrecarga presórica fue menor en el grupo Intermitente (p=0,001), comparada al grupo Convencional. Hubo aumento en el espesor del VD del grupo Intermitente, medida por el ecocardiograma, comparado a su momento basal (p<0,05). El índice de performance miocárdica del VD fue mejor en el grupo Intermitente (p=0,024), comparado al Convencional. Los grupos estimulados presentaron aumento de la masa muscular en comparación al grupo Control (p=0,001). No hubo diferencia en el contenido de agua miocárdica. CONCLUSIÓN: EL VP intermitente desarrolló hipertrofia de mejor desempeño funcional, sugiriendo este protocolo como método preferencial de preparación ventricular.

Bandagem reversível do tronco pulmonar IV: análise da hipertrofia aguda do ventrículo direito em modelo experimental de sobrecarga intermitente / IV Pulmonary trunk reversible banding: analysis of right ventricle acute hypertrophy in an intermittent loading experimental model

OBJETIVO: A bandagem ajustável do tronco pulmonar (TP) pode proporcionar treinamento ventricular mais fisiológico para cirurgia de Jatene em dois estágios. Este estudo experimental analisa a hipertrofia aguda (96 horas) do ventrículo direito (VD) submetido à sobrecarga sistólica intermitente. MÉTODOS: Cinco grupos de sete cabritos jovens foram dispostos conforme o tempo de sobrecarga sistólica do VD (0, 24, 48, 72 e 96 horas). O grupo zero hora funcionou como grupo controle. Avaliações ecocardiográficas e hemodinâmicas foram feitas diariamente. Os animais foram sacrificados para avaliação do conteúdo de água e pesagem das massas cardíacas. RESULTADOS: Houve aumento da espessura do VD a partir de 48 horas de treinamento (p<0,05) e rebaixamento da fração de ejeção do VD, com dilatação importante desta câmara nas primeiras 24 horas do protocolo, recuperando-se posteriormente. Houve aumento da relação volume/massa nas primeiras 24 horas do protocolo, em relação ao momento 96 horas (p=0,003). A massa do VD apresentou aumento de 104,7 por cento no grupo 96 horas em relação ao controle. Não houve diferença quanto ao conteúdo de água do VD. A média diária de aumento da massa do VD foi de 21,6 por cento ± 26,8 por cento. A taxa de ganho de massa muscular do VD para todo o período de estudo foi de 0,084 g/h ± 0,035 g/h. CONCLUSÃO: O protocolo de bandagem intermitente do TP permitiu ganho de massa muscular do VD, significativa no grupo de 96 horas de estudo. Esta hipertrofia não foi acompanhada de aumento no conteúdo de água, o que sugere maior síntese protéica nos tecidos cardíacos.

OBJECTIVES: Adjustable pulmonary trunk (PT) banding device may induce a more physiologic ventricle retraining for the two-stage Jatene operation. This experimental study evaluates the acute hypertrophy (96 hours) of the right ventricle (RV) submitted to an intermittent pressure overload. METHODS: Five groups of seven young goats were distributed according to RV intermittent systolic overload duration (0, 24, 48, 72 and 96 hours). The zero-hour group served as a control group. Echocardiographic and hemodynamic evaluations were performed daily. After completing the training program for each group, the animals were sacrificed for water content and cardiac masses evaluation. RESULTS: There was a significant increase in RV free wall thickness starting with the 48-hour group (p<0.05). However, a decreased RV ejection fraction, associated with an important RV dilation and a significant increase in the RV volume to mass ratio was observed at 24-hour training period, when compared to 96-hour period (p=0.003), with subsequent recovery throughout the protocol. A 104.7 percent increase in RV mass was observed in the 96-hour group, as compared to the control group, with no differences in water content between these two groups. The daily mean increase in RV mass during the study period was 21.6 percent ± 26.8 percent. The rate of RV mass acquisition for the overall study period of intermittent systolic overload was 0.084 g/h ± 0.035 g/h. CONCLUSION: Intermittent PT banding has allowed a significant RV mass acquisition in the 96-hour trained group. No myocardial water content changes were observed in this group, suggesting an increased myocardial protein synthesis.