RESUMEN
MicroRNAs (miRNAs) control RNA translation and are a class of small, tissue-specific, non-protein-coding RNAs that maintain cellular homeostasis through negative gene regulation. Maintenance of the physiological environment depends on the proper control of miRNA expression, as these molecules influence almost all genetic pathways, from the cell cycle checkpoint to cell proliferation and apoptosis, with a wide range of target genes. Dysregulation of the expression of miRNAs is correlated with several types of diseases, acting as regulators of cardiovascular functions, myogenesis, adipogenesis, osteogenesis, hepatic lipogenesis, and important brain functions. miRNAs can be modulated by environmental factors or external stimuli, such as physical exercise, and can eventually induce specific and adjusted changes in the transcriptional response. Physical exercise is used as a preventive and non-pharmacological treatment for many diseases. It is well established that physical exercise promotes various benefits in the human body such as muscle hypertrophy, mental health improvement, cellular apoptosis, weight loss, and inhibition of cell proliferation. This review highlights the current knowledge on the main miRNAs altered by exercise in the skeletal muscle, cardiac muscle, bone, adipose tissue, liver, brain, and body fluids. In addition, knowing the modifications induced by miRNAs and relating them to the results of prescribed physical exercise with different protocols and intensities can serve as markers of physical adaptation to training and responses to the effects of physical exercise for some types of chronic diseases. This narrative review consists of randomized exercise training experiments with humans and/or animals, combined with analyses of miRNA modulation.
Asunto(s)
MicroARNs , Adaptación Fisiológica , Animales , Ejercicio Físico/fisiología , Regulación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Músculo Esquelético/metabolismoRESUMEN
Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.
Asunto(s)
Angiotensina I/farmacología , Catalasa/metabolismo , Proteína Forkhead Box O3/metabolismo , Miocitos Cardíacos/patología , FN-kappa B/metabolismo , Fragmentos de Péptidos/farmacología , Superóxido Dismutasa-1/metabolismo , Triyodotironina/efectos adversos , Regulación hacia Arriba , Animales , Antioxidantes/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hipertrofia , Masculino , Modelos Biológicos , Miocitos Cardíacos/efectos de los fármacos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Sprague-Dawley , Ratas Transgénicas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Cardiac hypertrophy is an adaptive response to manage an excessive cardiac workload and maintain normal cardiac function. However, sustained hypertrophy leads to cardiomyopathy, cardiac failure, and death. Adrenergic receptors play a key role in regulating cardiac function under normal and pathological conditions. Mitochondria are responsible for 90% of ATP production in cardiomyocytes. Mitochondrial function is dynamically regulated by fusion and fission processes. Changes in mitochondrial dynamics and metabolism are central issues in cardiac hypertrophy. Stimulating cardiomyocytes with adrenergic agonists generates hypertrophy and increases mitochondrial fission, which in turn is associated with decreased ATP synthesis. Miro1 is a mitochondrial outer membrane protein involved in mitochondrial dynamics and transport in neurons. The objective of this work was to evaluate whether Miro1 regulates cardiomyocyte hypertrophy through changes in mitochondrial dynamics. In neonatal rat ventricular myocytes, we showed that phenylephrine induced cardiomyocyte hypertrophy and increased Miro1 mRNA and protein levels. Moreover, alpha-adrenergic stimulation provoked a mitochondrial fission pattern in the cardiomyocytes. Miro1 knockdown prevented both the cardiomyocyte hypertrophy and mitochondrial fission pattern. Our results suggest that Miro1 participates in phenylephrine-induced cardiomyocyte hypertrophy through mitochondrial fission.
Asunto(s)
Cardiomegalia/metabolismo , Proteínas Mitocondriales/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteínas de Unión al GTP rho/metabolismo , Animales , Animales Recién Nacidos , Cardiomegalia/patología , Regulación de la Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/citología , Dinámicas Mitocondriales , Proteínas Mitocondriales/genética , Fenilefrina/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Proteínas de Unión al GTP rho/genéticaRESUMEN
Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.
Asunto(s)
Cardiomegalia/etiología , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/etiología , Hipercolesterolemia/etiología , Resistencia a la Insulina , Obesidad/complicaciones , Receptor de Angiotensina Tipo 2/fisiología , Animales , Cardiomegalia/metabolismo , Cardiomegalia/patología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Leptina/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
Growth differentiation factor 11 (GDF11) is a novel factor with controversial effects on cardiac hypertrophy both in vivo and in vitro. Although recent evidence has corroborated that GDF11 prevents the development of cardiac hypertrophy, its molecular mechanism remains unclear. In our previous work, we showed that norepinephrine (NE), a physiological pro-hypertrophic agent, increases cytoplasmic Ca2+ levels accompanied by a loss of physical and functional communication between sarcoplasmic reticulum (SR) and mitochondria, with a subsequent reduction in the mitochondrial Ca2+ uptake and mitochondrial metabolism. In order to study the anti-hypertrophic mechanism of GDF11, our aim was to investigate whether GDF11 prevents the loss of SR-mitochondria communication triggered by NE. Our results show that: a) GDF11 prevents hypertrophy in cultured neonatal rat ventricular myocytes treated with NE. b) GDF11 attenuates the NE-induced loss of contact sites between both organelles. c) GDF11 increases oxidative mitochondrial metabolism by stimulating mitochondrial Ca2+ uptake. In conclusion, the GDF11-dependent maintenance of physical and functional communication between SR and mitochondria is critical to allow Ca2+ transfer between both organelles and energy metabolism in the cardiomyocyte and to avoid the activation of Ca2+-dependent pro-hypertrophic signaling pathways.
Asunto(s)
Cardiomegalia/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Mitocondrias Cardíacas/fisiología , Miocitos Cardíacos/metabolismo , Retículo Sarcoplasmático/fisiología , Animales , Animales Recién Nacidos , Calcio/metabolismo , Cardiomegalia/inducido químicamente , Comunicación Celular , Metabolismo Energético , Mitocondrias Cardíacas/metabolismo , Ratas Sprague-DawleyRESUMEN
Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-ß family, has been shown to act as a negative regulator in cardiac hypertrophy. Ca2+ signaling modulates cardiomyocyte growth; however, the role of Ca2+-dependent mechanisms in mediating the effects of GDF11 remains elusive. Here, we found that GDF11 induced intracellular Ca2+ increases in neonatal rat cardiomyocytes and that this response was blocked by chelating the intracellular Ca2+ with BAPTA-AM or by pretreatment with inhibitors of the inositol 1,4,5-trisphosphate (IP3) pathway. Moreover, GDF11 increased the phosphorylation levels and luciferase activity of Smad2/3 in a concentration-dependent manner, and the inhibition of IP3-dependent Ca2+ release abolished GDF11-induced Smad2/3 activity. To assess whether GDF11 exerted antihypertrophic effects by modulating Ca2+ signaling, cardiomyocytes were exposed to hypertrophic agents (100 nM testosterone or 50 µM phenylephrine) for 24 h. Both treatments increased cardiomyocyte size and [³H]-leucine incorporation, and these responses were significantly blunted by pretreatment with GDF11 over 24 h. Moreover, downregulation of Smad2 and Smad3 with siRNA was accompanied by inhibition of the antihypertrophic effects of GDF11. These results suggest that GDF11 modulates Ca2+ signaling and the Smad2/3 pathway to prevent cardiomyocyte hypertrophy.
Asunto(s)
Señalización del Calcio , Cardiomegalia/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Calcio/metabolismo , Células Cultivadas , Factores de Diferenciación de Crecimiento/genética , Miocitos Cardíacos/efectos de los fármacos , Fenilefrina/farmacología , Ratas , Ratas Sprague-Dawley , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Testosterona/farmacologíaRESUMEN
ABSTRACT Odanacatib (ODN) is a selective inhibitor of cathepsin K. The cysteine protease cathepsin K has been implicated in cardiac hypertrophy. Resistine is an adipokine which is identified to promote cardiac hypertrophy. Here, we hypothesize that ODN mitigates resistin-induced myocyte hypertrophy. Cell surface area and protein synthesis were measured after treatment with resistin and ODN in H9c2 cells. The expression of cardiomyocyte hypertrophy marker BNP and β-MHC was detected by RT-qPCR. The expression and phosphorylation of AMPK and LKB1 were analyzed with Western blot. Resistin could significantly increase cardiomyocyte cell surface area, protein synthesis, and embryonic gene BNP and β-MHC expression, inhibit phosphorylation of AMPK and LKB1. ODN could significantly reverse the effects of resistin. Collectively, our data suggest that ODN can inhibit cardiomyocyte hypertrophy induced by resistin and the underlying mechanism may be involved in LKB1/AMPK pathway.
RESUMEN
Previous studies have indicated that AMP-activated protein kinase (AMPK) plays a critical role in the control of cardiac hypertrophy mediated by different stimuli such as thyroid hormone (TH). Although the classical effects of TH mediating cardiac hypertrophy occur by transcriptional mechanisms, recent studies have identified other responses to TH, which are more rapid and take place in seconds or minutes evidencing that TH rapidly modulates distinct signaling pathway, which might contribute to the regulation of cardiomyocyte growth. Here, we evaluated the rapid effects of TH on AMPK signaling pathway in cultured cardiomyocytes and determined the involvement of AMPK in T3-induced cardiomyocyte growth. We found for the first time that T3 rapidly activated AMPK signaling pathway. The use of small interfering RNA against AMPK resulted in increased cardiomyocyte hypertrophy while the pharmacological stimulation of AMPK attenuated this process, demonstrating that AMPK contributes to regulation of T3-induced cardiomyocyte growth.