RESUMEN
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD+-dependent deacetylase SIRT1 is cardioprotective in response to severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could protect against ER-stress-induced cardiac damage. The purpose of this study was to identify natural molecules able to alleviate ER stress and inhibit cardiomyocyte cell death through SIRT1 activation. Several phenolic compounds, abundant in vegetables, fruits, cereals, wine, and tea, were reported to stimulate the deacetylase activity of SIRT1. Here, we evaluated the cardioprotective effect of ten of these phenolic compounds against severe ER stress using cardiomyoblast cells and mice. Among the molecules tested, we showed that ferulic acid, pterostilbene, and tyrosol significantly protect cardiomyocytes and mice heart from cardiac alterations induced by severe ER stress. By studying the mechanisms involved, we showed that the activation of the PERK/eIF2α/ATF4/CHOP pathway of the UPR was reduced by ferulic acid, pterostilbene, and tyrosol under ER stress conditions, leading to a reduction in cardiomyocyte apoptosis. The protection afforded by these phenolic compounds was not directly related to their antioxidant activity but rather to their ability to increase SIRT1-mediated deacetylation of eIF2α. Taken together, our results suggest that ferulic acid, pterostilbene, and tyrosol are promising molecules to activate SIRT1 to protect the heart from the adverse effects of ER stress.
Asunto(s)
Factor 2 Eucariótico de Iniciación , Sirtuina 1 , Animales , Apoptosis , Ácidos Cumáricos , Estrés del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Ratones , Alcohol Feniletílico/análogos & derivados , Sirtuina 1/metabolismo , Estilbenos , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismoRESUMEN
Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.
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Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Complejo Vitamínico B/farmacología , Animales , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Humanos , Miocardio/metabolismoRESUMEN
Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (Sirt1ciKO) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after Sirt1 deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in Sirt1ciKO mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function.
Asunto(s)
Cardiopatías/genética , Corazón , Presión , Sirtuina 1/genética , Sirtuina 1/metabolismo , Animales , Ecocardiografía , Fibrosis/patología , Eliminación de Gen , Cardiopatías/metabolismo , Cardiopatías/patología , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Miocitos Cardíacos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Tamoxifeno/efectos adversosRESUMEN
PGC-1α, a key regulator of energy metabolism, seems to be a relevant therapeutic target to rectify the energy deficit observed in heart failure (HF). Since our previous work has shown positive effects of cobalamin (Cb) on PGC-1α cascade, we investigate the protective role of Cb in pressure overload-induced myocardial dysfunction. Mice were fed with normal diet (ND) or with Cb and folate supplemented diet (SD) 3weeks before and 4weeks after transverse aortic constriction (TAC). At the end, left ventricle hypertrophy and drop of ejection fraction were significantly lower in SD mice than in ND mice. Alterations in mitochondrial oxidative capacity, fatty acid oxidation and mitochondrial biogenesis transcription cascade were markedly improved by SD. In SD-TAC mice, lower expression level of the acetyltransferase GCN5 and upregulation of the methyltransferase PRMT1 were associated with a lower protein acetylation and a higher protein methylation levels. This was accompanied by a sustained expression of genes involved in mitochondrial biogenesis transcription cascade (Tfam, Nrf2, Cox1 and Cox4) after TAC in SD mice, suggesting a preserved activation of PGC-1α; this could be at least partly due to corrected acetylation/methylation status of this co-activator. The beneficial effect of the treatment would not be due to an effect of Cb and folate on oxidative stress or on homocysteinemia, which were unchanged by SD. These results showed that Cb and folate could protect the failing heart by preserving energy status through maintenance of mitochondrial biogenesis. It reinforces the concept of a metabolic therapy of HF.
Asunto(s)
Ácido Fólico/farmacología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Contracción Miocárdica/efectos de los fármacos , Vitamina B 12/farmacología , Animales , Biomarcadores , Células Cultivadas , Suplementos Dietéticos , Modelos Animales de Enfermedad , Metabolismo Energético , Insuficiencia Cardíaca/patología , Hiperhomocisteinemia/metabolismo , Ratones , Modelos Biológicos , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Oxidación-Reducción , Estrés OxidativoRESUMEN
It is increasingly acknowledged that a sex and gender specificity affects the occurrence, development, and consequence of a plethora of pathologies. Mitochondria are considered as the powerhouse of the cell because they produce the majority of energy-rich phosphate bonds in the form of adenosine tri-phosphate (ATP) but they also participate in many other functions like steroid hormone synthesis, reactive oxygen species (ROS) production, ionic regulation, and cell death. Adequate cellular energy supply and survival depend on mitochondrial life cycle, a process involving mitochondrial biogenesis, dynamics, and quality control via mitophagy. It appears that mitochondria are the place of marked sexual dimorphism involving mainly oxidative capacities, calcium handling, and resistance to oxidative stress. In turn, sex hormones regulate mitochondrial function and biogenesis. Mutations in genes encoding mitochondrial proteins are the origin of serious mitochondrial genetic diseases. Mitochondrial dysfunction is also an important parameter for a large panel of pathologies including neuromuscular disorders, encephalopathies, cardiovascular diseases (CVDs), metabolic disorders, neuropathies, renal dysfunction etc. Many of these pathologies present sex/gender specificity. Here we review the sexual dimorphism of mitochondria from different tissues and how this dimorphism takes part in the sex specificity of important pathologies mainly CVDs and neurological disorders.
Asunto(s)
Adenosina Trifosfato/biosíntesis , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores Sexuales , Apoptosis , Femenino , Humanos , Masculino , Mitocondrias/fisiología , Enfermedades Mitocondriales/fisiopatología , Modelos BiológicosRESUMEN
Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders.
Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Hipotálamo/metabolismo , Animales , Metabolismo de los Hidratos de Carbono/fisiología , Ingestión de Alimentos/fisiología , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Masculino , Ratones , Músculo Esquelético/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Páncreas/metabolismo , Aumento de Peso/fisiologíaRESUMEN
Scarring and remodeling of the left ventricle (LV) after myocardial infarction (MI) results in ischemic cardiomyopathy with reduced contractile function. Regional differences related to persisting ischemia may exist. We investigated the hypothesis that mitochondrial function and structure is altered in the myocardium adjacent to MI with reduced perfusion (MIadjacent) and less so in the remote, nonischemic myocardium (MIremote). We used a pig model of chronic coronary stenosis and MI (n = 13). Functional and perfusion MR imaging 6 wk after intervention showed reduced ejection fraction and increased global wall stress compared with sham-operated animals (Sham; n = 14). Regional strain in MIadjacent was reduced with reduced contractile reserve; in MIremote strain was also reduced but responsive to dobutamine and perfusion was normal compared with Sham. Capillary density was unchanged. Cardiac myocytes isolated from both regions had reduced basal and maximal oxygen consumption rate, as well as through complex I and II, but complex IV activity was unchanged. Reduced respiration was not associated with detectable reduction of mitochondrial density. There was no significant change in AMPK or glucose transporter expression levels, but glycogen content was significantly increased in both MIadjacent and MIremote Glycogen accumulation was predominantly perinuclear; mitochondria in this area were smaller but only in MIadjacent where also subsarcolemmal mitochondria were smaller. In conclusion, after MI reduction of mitochondrial respiration and glycogen accumulation occur in all LV regions suggesting that reduced perfusion does not lead to additional specific changes and that increased hemodynamic load is the major driver for changes in mitochondrial function.
Asunto(s)
Cardiomiopatías/metabolismo , Mitocondrias Cardíacas/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Consumo de Oxígeno , Remodelación Ventricular , Proteínas Quinasas Activadas por AMP/genética , Animales , Western Blotting , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/etiología , Cardiomiopatías/patología , Respiración de la Célula , Cicatriz , Estenosis Coronaria/complicaciones , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Glucógeno/metabolismo , Imagen por Resonancia Magnética , Microscopía Electrónica , Microscopía Fluorescente , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/etiología , Infarto del Miocardio/patología , Imagen de Perfusión Miocárdica , Miocitos Cardíacos/ultraestructura , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Volumen Sistólico , Sus scrofa , PorcinosRESUMEN
Creatine kinase content, isoform distribution, and participation in energy transfer are muscle type specific. We analysed ultrastructural changes in slow muscle fibres of soleus due to invalidation of creatine kinase (CK) to reveal a difference in the remodelling strategy in comparison with fast muscle fibres of gastrocnemius published previously. We have employed the stereological method of vertical sections and electron microscopy of soleus muscles of wild type (WT) and CK-/- mice. The mitochondrial volume density was 1.4× higher but that of sarcoplasmic reticulum (SR) was almost 5× lower in slow CK-/- muscles fibres than in WT fibres. The volume density of terminal cisterns and of t-tubules was also lower in CK-/- than in WT fibres. The analysis of organelle environment revealed increased neighbourhood of mitochondria and A-bands that resulted from the decreased volume density of SR, from relocation of mitochondria along myofibrils, and from intrusion of mitochondria to myofibrils. These processes direct ATP supply closer to the contractile machinery. The decreased interaction between mitochondria and SR suggests reduced dependence of calcium uptake on oxidative ATP production. In conclusion, the architecture of skeletal muscle cells is under control of a cellular program that optimizes energy utilization specifically for a given muscle type.
Asunto(s)
Creatina Quinasa/deficiencia , Mitocondrias Musculares/ultraestructura , Fibras Musculares de Contracción Lenta/enzimología , Fibras Musculares de Contracción Lenta/ultraestructura , Retículo Sarcoplasmático/enzimología , Retículo Sarcoplasmático/ultraestructura , Animales , Células Cultivadas , Creatina Quinasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/patología , Fibras Musculares de Contracción Lenta/patología , Retículo Sarcoplasmático/patologíaRESUMEN
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.-Lantier, L., Fentz, J., Mounier, R., Leclerc, J., Treebak, J. T., Pehmøller, C., Sanz, N., Sakakibara, I., Saint-Amand, E., Rimbaud, S., Maire, P., Marette, A., Ventura-Clapier, R., Ferry, A., Wojtaszewski, J. F. P., Foretz, M., Viollet, B. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Resistencia Física/fisiología , Animales , Glucosa/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Muscular/fisiología , Fatiga Muscular/fisiología , Oxidación-Reducción , Fosforilación/fisiología , Condicionamiento Físico AnimalRESUMEN
Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparß, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.
Asunto(s)
Receptores de Activinas Tipo II/antagonistas & inhibidores , Fragmentos Fc de Inmunoglobulinas/farmacología , Músculos/fisiopatología , Distrofia Muscular Animal/fisiopatología , Animales , Línea Celular , Metabolismo Energético/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos mdx , Porinas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Calcium pumping into the endoplasmic reticulum (ER) lumen is thought to be coupled to a countertransport of protons through sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) and the members of the ClC family of chloride channels. However, pH in the ER lumen remains neutral, which suggests a mechanism responsible for proton re-entry. We studied whether cation-proton exchangers could act as routes for such a re-entry. ER Ca(2+) uptake was measured in permeabilized immortalized hypothalamic neurons, primary rat cortical neurons and mouse cardiac fibers. Replacement of K(+) in the uptake solution with Na(+) or tetraethylammonium led to a strong inhibition of Ca(2+) uptake in neurons and cardiomyocytes. Furthermore, inhibitors of the potassium-proton exchanger (quinine or propranolol) but not of the sodium-proton exchanger reduced ER Ca(2+) uptake by 56-82%. Externally added nigericin, a potassium-proton exchanger, attenuated the inhibitory effect of propranolol. Inhibitors of small conductance calcium-sensitive K(+) (SK(Ca)) channels (UCL 1684, dequalinium) blocked the uptake of Ca(2+) by the ER in all preparations by 48-94%, whereas inhibitors of other K(+) channels (IK(Ca), BK(Ca) and K(ATP)) had no effect. Fluorescence microscopy and western blot analysis revealed the presence of both SK(Ca) channels and the potassium-proton exchanger leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) in ER in situ and in the purified ER fraction. The data obtained demonstrate that SK(Ca) channels and LETM1 reside in the ER membrane and that their activity is essential for ER Ca(2+) uptake.
Asunto(s)
Retículo Endoplásmico/metabolismo , Miocitos Cardíacos/metabolismo , Neuronas/metabolismo , Antiportadores de Potasio-Hidrógeno/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Animales , Calcio/metabolismo , Células Cultivadas , Transporte Iónico/efectos de los fármacos , Ratones , Modelos Biológicos , Miocitos Cardíacos/efectos de los fármacos , Neuronas/efectos de los fármacos , Nigericina/farmacología , Antiportadores de Potasio-Hidrógeno/antagonistas & inhibidores , Propranolol/farmacología , Ratas , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/antagonistas & inhibidoresRESUMEN
Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn(-/-) mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn(-/-) mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn(-/-) mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn(-/-) mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.
Asunto(s)
Metabolismo Energético , Contracción Muscular , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Resistencia Física , Animales , Genotipo , Glucólisis , Ácido Láctico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Musculares/metabolismo , Fatiga Muscular , Miostatina/deficiencia , Miostatina/genética , Consumo de Oxígeno , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Fenotipo , Fosfopiruvato Hidratasa/metabolismo , Carrera , Transducción de Señal , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The concept of skeletal muscle myopathy as a main determinant of exercise intolerance in chronic heart failure (HF) is gaining acceptance. Symptoms that typify HF patients, including shortness of breath and fatigue, are often directly related to the abnormalities of the skeletal muscle in HF. Besides muscular wasting, alterations in skeletal muscle energy metabolism, including insulin resistance, have been implicated in HF. Adiponectin, an adipocytokine with insulin-sensitizing properties, receives increasing interest in HF. Circulating adiponectin levels are elevated in HF patients, but high levels are paradoxically associated with poor outcome. Previous analysis of m. vastus lateralis biopsies in HF patients highlighted a striking functional adiponectin resistance. Together with increased circulating adiponectin levels, adiponectin expression within the skeletal muscle is elevated in HF patients, whereas the expression of the main adiponectin receptor and genes involved in the downstream pathway of lipid and glucose metabolism is downregulated. In addition, the adiponectin-related metabolic disturbances strongly correlate with aerobic capacity (VO2 peak), sub-maximal exercise performance and muscle strength. These observations strengthen our hypothesis that adiponectin and its receptors play a key role in the development and progression of the "heart failure myopathy". The question whether adiponectin exerts beneficial rather than detrimental effects in HF is still left unanswered. This current research overview will elucidate the emerging role of adiponectin in HF and suggests potential therapeutic targets to tackle energy wasting in these patients.
Asunto(s)
Adiponectina/fisiología , Metabolismo Energético , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , HumanosRESUMEN
The beta-adrenergic system is a potent stimulus for enhancing cardiac output that may become deleterious when energy metabolism is compromised as in heart failure. We thus examined whether the AMP-activated protein kinase (AMPK) that is activated in response to energy depletion may control the beta-adrenergic pathway. We studied the cardiac response to beta-adrenergic stimulation of AMPKα2-/- mice or to pharmacological AMPK activation on contractile function, calcium current, cAMP content and expression of adenylyl cyclase 5 (AC5), a rate limiting step of the beta-adrenergic pathway. In AMPKα2-/- mice the expression of AC5 (+50%), the dose response curve of left ventricular developed pressure to isoprenaline (p<0.001) or the response to forskolin, an activator of AC (+25%), were significantly increased compared to WT heart. Similarly, the response of L-type calcium current to 3-isobutyl-l-methylxanthine (IBMX), a phosphodiesterase inhibitor was significantly higher in KO (+98%, p<0.01) than WT (+57%) isolated cardiomyocytes. Conversely, pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) induced a 45% decrease in AC5 expression (p<0.001) and a 40% decrease of cAMP content (P<0.001) as measured by fluorescence resonance energy transfer (FRET) compared to unstimulated rat cardiomyocytes. Finally, in experimental pressure overload-induced cardiac dysfunction, AMPK activation was associated with a decreased expression of AC5 that was blunted in AMPKα2-/- mice. The results show that AMPK activation down-regulates AC5 expression and blunts the beta-adrenergic cascade. This crosstalk between AMPK and beta-adrenergic pathways may participate in a compensatory energy sparing mechanism in dysfunctional myocardium.
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Proteínas Quinasas Activadas por AMP , Insuficiencia Cardíaca , Ratones , Ratas , Animales , Calcio , Miocitos Cardíacos , Adrenérgicos , Calcio de la DietaRESUMEN
The heart is responsible for pumping blood throughout the blood vessels to the periphery by repeated, rhythmic contractions at variable intensity. As such the heart should permanently adjust energy production to energy utilization and is a high-energy consumer. For this the heart mainly depends on oxidative metabolism for adequate energy production and on efficient energy transfer systems. In heart failure, there is disequilibrium between the work the heart has to perform and the energy it is able to produce to fulfill its needs. This has led to the concept of energy starvation of the failing heart. This includes decreased oxygen and substrate supply, altered substrate utilization, decreased energy production by mitochondria and glycolysis, altered energy transfer and inefficient energy utilization. Mitochondrial biogenesis and its transcription cascade are down-regulated. Disorganization of the cytoarchitecture of the failing cardiomyocyte also participates in energy wastage. Finally, the failing of the cardiac pump, by decreasing oxygen and substrate supply, leads to a systemic energy starvation. Metabolic therapy has thus emerged as an original and promising approach in the treatment heart failure. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.
Asunto(s)
Metabolismo Energético , Insuficiencia Cardíaca/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Ácidos Grasos/metabolismo , Glucólisis , Corazón/fisiopatología , Humanos , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/patologíaRESUMEN
The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg·kg(-1)·day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg·kg(-1)·day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT-PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline-induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening.
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Cardiomegalia/tratamiento farmacológico , Cardiotónicos/farmacología , Curcumina/farmacología , Isoproterenol/toxicidad , Enfermedades Mitocondriales/tratamiento farmacológico , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Agonistas Adrenérgicos beta/toxicidad , Animales , Apoptosis/efectos de los fármacos , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Catecolaminas/metabolismo , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Masculino , Enfermedades Mitocondriales/inducido químicamente , Enfermedades Mitocondriales/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Miocarditis/inducido químicamente , Miocarditis/tratamiento farmacológico , Miocarditis/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Recent studies have shown that long-term cocaine use induces diastolic impairment and a myocardial oxidative stress. Recently, we have reported that cocaine-induced cardiac dysfunction may be due to a mitochondrial reactive oxygen species (ROS) overproduction, which occurs at the same time as xanthine oxidase (XO) activation. In this work, we hypothesized that XO activation contributes to mitochondrial ROS overproduction, which in turn contributes to diastolic dysfunction. To test this, we used a well-established in vivo model of cocaine-induced diastolic dysfunction. In this experimental model treated with or without allopurinol, an inhibitor of XO, we measured mitochondrial ROS production and function. Mitochondrial alterations were characterized by an increase in oxygen consumption through complexes I and III, a reduction in ATP production, and an increased ROS production specifically in isolated interfibrillar mitochondria. Allopurinol treatment prevented the rise in mitochondrial ROS levels and the decrease in ATP production. In the same way, allopurinol treatment improved ventricular relaxation with a decrease in Tau, an index of left ventricle relaxation and of end-diastolic pressure volume relation. These results confirmed the critical role of XO in the sequence of events leading to cocaine-induced cardiac dysfunction.
Asunto(s)
Cocaína , Mitocondrias Cardíacas/enzimología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Función Ventricular Izquierda , Xantina Oxidasa/metabolismo , Adenosina Trifosfato/metabolismo , Alopurinol/farmacología , Animales , Antioxidantes/farmacología , Diástole , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/metabolismo , Complejo III de Transporte de Electrones/metabolismo , Metabolismo Energético , Inhibidores Enzimáticos/farmacología , Hemodinámica , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxidos/metabolismo , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
FAT/CD36 (fatty acid translocase/Cluster of Differentiation 36), a plasma membrane fatty-acid transport protein, has been found on mitochondrial membranes; however, it remains unclear where FAT/CD36 resides on this organelle or its functional role within mitochondria. In the present study, we demonstrate, using several different approaches, that in skeletal muscle FAT/CD36 resides on the OMM (outer mitochondrial membrane). To determine the functional role of mitochondrial FAT/CD36 in this tissue, we determined oxygen consumption rates in permeabilized muscle fibres in WT (wild-type) and FAT/CD36-KO (knockout) mice using a variety of substrates. Despite comparable muscle mitochondrial content, as assessed by unaltered mtDNA (mitochondrial DNA), citrate synthase, ß-hydroxyacyl-CoA dehydrogenase, cytochrome c oxidase complex IV and respiratory capacities [maximal OXPHOS (oxidative phosphorylation) respiration] in WT and KO mice, palmitate-supported respiration was 34% lower in KO animals. In contrast, palmitoyl-CoA-supported respiration was unchanged. These results indicate that FAT/CD36 is key for palmitate-supported respiration. Therefore we propose a working model of mitochondrial fatty-acid transport, in which FAT/CD36 is positioned on the OMM, upstream of long-chain acyl-CoA synthetase, thereby contributing to the regulation of mitochondrial fatty-acid transport. We further support this model by providing evidence that FAT/CD36 is not located in mitochondrial contact sites, and therefore does not directly interact with carnitine palmitoyltransferase-I as original proposed.
Asunto(s)
Antígenos CD36/análisis , Membranas Mitocondriales/metabolismo , Palmitatos/metabolismo , Acilcoenzima A/metabolismo , Animales , Antígenos CD36/genética , Antígenos CD36/metabolismo , Coenzima A Ligasas/metabolismo , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Músculo Esquelético/metabolismo , Oxidación-Reducción , RatasRESUMEN
Calcineurin is a protein phosphatase that is uniquely regulated by sustained increases in intracellular Ca(2+) following signal transduction events. Calcineurin controls cellular proliferation, differentiation, apoptosis, and inducible gene expression following stress and neuroendocrine stimulation. In the adult heart, calcineurin regulates hypertrophic growth of cardiomyocytes in response to pathologic insults that are associated with altered Ca(2+) handling. Here we determined that calcineurin signaling is directly linked to the proper control of cardiac contractility, rhythm, and the expression of Ca(2+)-handling genes in the heart. Our approach involved a cardiomyocyte-specific deletion using a CnB1-LoxP-targeted allele in mice and three different cardiac-expressing Cre alleles/transgenes. Deletion of calcineurin with the Nkx2.5-Cre knock-in allele resulted in lethality at 1 day after birth due to altered right ventricular morphogenesis, reduced ventricular trabeculation, septal defects, and valvular overgrowth. Slightly later deletion of calcineurin with the alpha-myosin heavy chain Cre transgene resulted in lethality in early mid adulthood that was characterized by substantial reductions in cardiac contractility, severe arrhythmia, and reduced myocyte content in the heart. Young calcineurin heart-deleted mice died suddenly after pressure overload stimulation or neuroendocrine agonist infusion, and telemetric monitoring of older mice showed arrhythmia leading to sudden death. Mechanistically, loss of calcineurin reduced expression of key Ca(2+)-handling genes that likely lead to arrhythmia and reduced contractility. Loss of calcineurin also directly impacted cellular proliferation in the postnatal developing heart. These results reveal multiple mechanisms whereby calcineurin regulates cardiac development and myocyte contractility.