Christophe Beauloye

The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. In addition, insulin participates in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity. Significant advancements have been made over the last 20 years in the understanding of the signal transduction elements involved in these insulin effects. Among these molecular mechanisms, the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway is thought to play a crucial role. Under pathological conditions, such as type-2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified. These molecular signalling alterations are often linked to atypical crosstalks with other signal transduction pathways. On the other hand, pharmacological modifications of parallel and interdependent signalling components, such as the AMP-activated protein kinase pathway, are now considered to be a good therapeutic approach to treat insulin-signalling defects such as insulin resistance and type-2 diabetes. In this review, we will focus on the description of the molecular signalling elements involved in insulin action in the heart and vasculature under these different physiological, pathological, and therapeutical conditions.

Heart failure is a progressive muscular disorder leading to a deterioration of the heart characterized by a contractile dysfunction and a chronic energy deficit. As a consequence, the failing heart is unable to meet the normal metabolic and energy needs of the body. The transition between compensated left ventricular hypertrophy and the de-compensated heart is multifactorial, although metabolic disturbances are considered to play a significant role. In this respect, the AMP-activated protein kinase (AMPK) could be a potential target in heart failure development. AMPK senses the energy state of the cell and orchestrates a global metabolic response to energy deprivation. We briefly review here the current knowledge about the chronic energy deficit of the failing heart, as well as the role of AMPK in energy homeostasis and in the control of non-metabolic targets in relation to cardiac hypertrophy and heart failure. The relative importance of energetic and non-metabolic effects in the potential cardioprotective action of AMPK is discussed.

Protein O-GlcNAcylation is increasingly recognized as an important cellular regulatory mechanism, in multiple organs including the heart. However, the mechanisms leading to O-GlcNAcylation in mitochondria and the consequences on their function remain poorly understood. In this study, we use an in vitro reconstitution assay to characterize the intra-mitochondrial O-GlcNAc system without potential cytoplasmic confounding effects. We compare the O-GlcNAcylome of isolated cardiac mitochondria with that of mitochondria acutely exposed to NButGT, a specific inhibitor of glycoside hydrolase. Amongst the 409 O-GlcNAcylated mitochondrial proteins identified, 191 display increased O-GlcNAcylation in response to NButGT. This is associated with enhanced Complex I (CI) activity, increased maximal respiration in presence of pyruvate-malate, and a striking reduction of mitochondrial ROS release, which could be related to O-GlcNAcylation of specific subunits of ETC complexes (CI, CIII) and TCA cycle enzymes. In conclusion, our work underlines the existence of a dynamic mitochondrial O-GlcNAcylation system capable of rapidly modifying mitochondrial function.

Heart failure (HF) represents a multifaceted clinical syndrome characterized by the heart's inability to pump blood efficiently to meet the body's metabolic demands. Despite advances in medical management, HF remains a major cause of morbidity and mortality worldwide. In recent years, considerable attention has been directed toward understanding the molecular mechanisms underlying HF pathogenesis, with a particular focus on the role of AMP-activated protein kinase (AMPK) and protein O-GlcNAcylation. This review comprehensively examines the current understanding of AMPK and O-GlcNAcylation signalling pathways in HF, emphasizing their interplay and dysregulation. We delve into the intricate molecular mechanisms by which AMPK and O-GlcNAcylation contribute to cardiac energetics, metabolism, and remodelling, highlighting recent preclinical and clinical studies that have explored novel therapeutic interventions targeting these pathways.

Background Left atrial structural remodeling contributes to the persistence of atrial fibrillation (AF) and influences the outcomes of catheter ablation (CA). We investigated the usefulness of 18 F‐fluorodeoxyglucose‐positron emission tomography in detecting low atrial glucose uptake (LGU) as a potential marker of fibrosis and its predictive value for CA success in persistent AF. Methods Thirty‐six patients without diabetes with persistent AF scheduled for CA underwent nicotinic acid‐stimulated 18 F‐fluorodeoxyglucose‐positron emission tomography to assess global and segmental LGU before CA. LGU was compared with low voltage areas on electroanatomical mapping, left atrial volume index via echocardiography, and late gadolinium enhancement from cardiac magnetic resonance imaging as indicators of fibrosis. Patients were followed for up to 24 months post CA to assess AF recurrence. Results Global LGU extent was 16.8% (7.6–42.6) and correlated with left atrial volume index (R 2 =0.20, P =0.039) and low voltage area during AF and right atrial pacing (R 2 =0.54 and R 2 =0.35 respectively, both P <0.001). Multivariable analysis showed that LGU significantly predicted moderate/severe low voltage area remodeling ( P <0.001) with an area under the curve of 0.78 (95% CI, 0.58–0.97), independent of clinical and imaging parameters. AF recurred in 50% of patients. LGU >17%, but not late gadolinium enhancement, predicted AF recurrence ( P =0.026; AUC, 0.67 [95% CI, 0.48–0.86]). Conclusions Nicotinic acid‐enhanced 18 F‐fluorodeoxyglucose‐positron emission tomography LGU extent reflects fibrosis by low voltage areas and predicts AF recurrence after CA in patients with persistent AF. This suggests that it could serve as a noninvasive tool for assessing atrial fibrosis and remodeling in atrial cardiomyopathy due to persistent AF.