Contribution Of Impaired Myocardial Insulin Signaling To Mitochondrial Dysfunction And Oxidative Stress In The Heart

Background—Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to LV dysfunction. The contribution of altered myocardial insulin action, independently of associated changes in systemic metabolism is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function. Methods and Results—In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrates glutamate and the fatty acid derivative palmitoyl carnitine (PC) were observed. Mitochondria were also uncoupled when exposed to PC due in part to increased ROS production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reduction in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in TCA cycle and FA oxidation proteins in mitochondria, suggest that defects in FA and pyruvate metabolism and TCA flux may explain the mitochondrial dysfunction observed. Conclusions—Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which together with reduced TCA and FA oxidative capacity impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart

Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress

Implication du canal potassique dans la protection du myocarde vis-à-vis de l'ischémie

L'insuffisance cardiaque est la première cause de mortalité en France. L'ischémie myocardique secondaire à l'athérosclérose coronaire en est l'étiologie principale. Les différentes stratégies de revascularisation , ou les thérapeutiques médicamenteuses utilisées en pratique clinique pour traiter l'ischémie visent principalement à améliorer la perfusion et/ou à réduire les besoins énergétiques du myocarde grâce à une action hémodynamique. Si ces traitements sont parfois très efficaces sur les symptomes, ils n'ont que peu d'intérêt pronostique. L'amélioration de la prise en charge de cette maladie passe maintenant par le développement de la recherche dans le domaine de la cytoprotection, de manière à proposer de nouvelles stratégies thérapeutiques visant à protéger le myocarde des lésions d'ischémie-reperfusion indépendamment de toute action hémodynamique. Le phénomène du préconditionnement ischémique (PCI) est à l'heure actuelle le moyen le plus efficace de protection myocardique endogène contre l'ischémie. Il est néammoins évident que le PCI ne peut pas être utilisé en pratique clinique pour traiter les patients souffrant d'une cardiomyopathie ischémique. Cependant, une meilleure compréhension de son mécanisme est de première importance afin d'identifier les cibles pharmacologiques de cette cardioprotection. Des travaux récents décrivent l'importance du canal potassique ATP-dépendant mitochondrial (mitoKATP) dans la voie de signalisation du PCI. Si son effet cardioprotecteur est maintenant communément admis, le mécanisme par lequel ce canal agit demeure inconnu. Le but de ce travail était d'élucider le rôle et le mécanisme d'action du mitoKATP dans l'ischémie afin de développer des drogues cardioprotectrices ciblant ce canal et conférant une cardioprotection contre l'ischémie. Les rôles possibles du PCI ou de l'ouverture du mitoKATP dans la préservation des fonctions cardiaque et mitochondriale ont été étudiés sur le modèle d'ischémie aiguë-reperfusion. Afin de se rapprocher de la maladie ischémique telle qu'elle se manifeste chez l'homme, un modèle d'ischémie chronique, obtenu par sténose extrinsèque de l'artère coronaire gauche chez le rat, a été réalisé. Sur ce dernier, une approche thérapeutique impliquant le mitoKATP a été étudiée. Méthodes : la fonction contractile a été étudiée sur coeur isolé et perfusé selon la technique de Langendorff et la fonction mitochondriale sur fibres pelées perméabilisées. Nos résultats révèlent l'existence d'altérations mitochondriales suite à l'ischémie aigue-reperfusion ou à l'ishémie chronique. Ces dysfonctions sont caractérisées par une baisse des paramètres respiratoires, une altération de la perméabilité de la membrane mitochondriale externe au cytochrome c et aux nucléotides, ainsi qu'une baisse de l'efficacité du couplage fonctionnel entre la créatine kinase mitochondriale et l'adénine nucléotide translocase. En situation d'ischémie aigue-reperfusion, ces altérations sont prévenues par un protocole de PCI ou après utilisation d'un ouvreur spécifique (le diazoxide) du mitoKATP. En situation d'ischémie chronique, le traitement chronique des rats par le diazoxide, améliore les fonctions contractile et mitchondriale altérées par ce type d'ischémie. En conclusion, l'ouverture du mitoKATP est bénéfique pour le coeur en situation d'ischémie et passe par la préservation de la structure-fonction de la mitochondrie.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure

This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions

Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart.

International audienceThe aim of this study was to investigate mitochondrial alterations in an animal model of chronic myocardial ischemia in rats obtained by surgical constriction of the left coronary artery. Resting coronary blood flow was measured using the fluorescent microsphere technique. Contractile function, defined by rate-pressure product, and myocardial oxygen consumption were measured in a Langendorff preparation. The mitochondrial function was evaluated on permeabilized skinned fibers. Three weeks after surgery, ischemic hearts showed a significant decrease in coronary blood flow compared with sham. Hemodynamic measurements showed a significant systolic and diastolic dysfunction. Alterations in mitochondrial function in ischemic hearts were mainly characterized by a significant decrease in the maximal velocity and apparent half-saturation constant for ADP, loss of the stimulatory effect of creatine, and a stimulatory effect of exogenous cytochrome c. These functional alterations were supported by structural alterations characterized by mitochondrial clustering and swelling associated with membrane rupture. We conclude that the alterations in systolic function after chronic ischemia are supported by severe modifications of mitochondrial structure and function