Biology subjects

Bouzin, C.

Publications and source records attributed to Bouzin, C..

4 recordsLinked to original sources

bioRxiv2025

skNAC is a Key Driver of Cardiomyocyte Integrity Against Pathological Cardiac Hypertrophy and Heart Failure

Chronic pressure overload induces cardiac hypertrophy and heart failure through coordinated alterations in proteome homeostasis, metabolism and sarcomere organisation. The muscle-specific -isoform of the nascent polypeptide-associated complex (skNAC) is essential for sarcomere assembly during development, but its role in adult hearts remains largely unknown. Here, we show that skNAC expression is reduced in hypertrophic cardiomyocytes, mouse models of pressure overload, and human hypertrophic hearts, in association with disease severity. Cardiomyocyte-specific skNAC deletion results in basal hypertrophy, systolic dysfunction, and premature death, and exacerbates pressure overload-induced heart failure. At the molecular level, skNAC associates with ribosomes and is required for sarcomere organisation maintenance, while its loss induces autophagy and ultrastructural defects. Integrated transcriptomic and proteomic analyses reveal early downregulation of metabolic gene expression despite increased abundance of corresponding proteins, indicating compensatory metabolic responses. Gain-of-function studies confirm a protective role against hypertrophy. Together, these data establish skNAC as a key regulator of cardiac proteome homeostasis and metabolic adaptation during pathological remodelling.

physiology↗

bioRxiv2024

A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling and diastolic dysfunction in C57Bl/6J and C57Bl/6N substrains

The prevalence of metabolic syndrome in cardiac diseases such as heart failure with preserved ejection fraction (HFpEF) prompts the scientific community to investigate its adverse effects on cardiac function and remodeling and its associated mechanisms. However, the choice of a preclinical model of obesity-induced cardiac remodeling has proven more challenging with inconsistencies often found in very similar mouse models. Here, we invesgated the implication of both genetic background of mouse substrains as well as diet composition to identify a suitable model of diet-induced cardiac alterations. C57Bl/6J and C57Bl/6N male mice were subjected to distinct obesogenic diets consisting of high-fat and moderate-sucrose content (HF-S) or High-Sucrose and moderate lipid content (F-HS) versus matching control diets. 5-month dietary intervention with obesogenic diets induced weight gain, adipocyte hypertrophy and increased visceral and subcutaneous fat mass in both substrains. Obese mice showed similar impairment of glucose disposition and insulin tolerance among genotypes, both strains developing insulin resistance within two months. However, echocardiographic follow-up and histological analysis confirmed that HF-S diet increases cardiac hypertrophy, interstitial fibrosis as well as le atrial area in the C57Bl/6J strain only. On the contrary C57Bl/6N exhibit cardiac eccentric remodeling under control diets, possibly owing to a genetic mutation in the myosin light chain kinase 3 (Mylk3) gene, specific to this substrain, which was not further enhanced under obesogenic diets. Altogether, the present results highlight the importance of carefully selecting the suitable mouse strain and diets to model diet-induced cardiac remodeling. In this regard, C57Bl/6J mice develop significant cardiac remodeling in response to HF-S, and seem a suitable model for cardiometabolic disease.

physiology↗

bioRxiv2023

A NRF2/beta3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress

BackgroundCardiac {beta}3-adrenergic receptors ({beta}3AR) are upregulated in diseased hearts and mediate antithetic effects to those of {beta}1AR and {beta}2AR. {beta}3AR agonists were recently shown to protect from myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. The underlying mechanisms, however, remain elusive. MethodsTo dissect functional, transcriptional and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human ADRB3 transgene ({beta}3AR-Tg) and subjected to transverse aortic constriction (TAC) were assessed using echocardiography, RNAseq, PET scan, metabolomics, seahorse and metabolic flux analysis. Subsequently, signaling and metabolic pathways were investigated further in vivo in {beta}3AR-Tg and in vitro in neonatal rat ventricular myocytes adenovirally infected to express {beta}3AR and subjected to neurohormonal stress. These results were completed with an analysis of single nucleus RNAseq data from human cardiac myocytes from heart failure patients. ResultsCompared with WT littermate, {beta}3AR-Tg mice were protected from hypertrophy after transaortic constriction (TAC), while systolic function was preserved. {beta}3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the Pentose-Phosphate Pathway (PPP) in {beta}3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the PPP, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, while downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in {beta}3AR-Tg post-TAC compared to WT, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as upstream transcription factor which was functionally verified in {beta}3AR-expressing cardiac myocytes where its translocation and nuclear activity was dependent on {beta}3AR activation of nitric-oxide synthase (NOS) NO production. ConclusionModerate expression of cardiac {beta}3AR, at levels observed in human cardiac myocardium, exerts antioxidant effects through activation of the PPP and NRF2 pathway, thereby preserving myocardial oxidative metabolism, function and integrity under pathophysiological stress.

physiology↗

bioRxiv2023

Sodium myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis in pressure overloaded mouse hearts

AimsRecent clinical studies have reported that myo-inositol is consistently elevated in plasma of patients with heart failure (HF), yet its role in cardiac dysfunction remains poorly understood. Myo-inositol is specifically transported into cells by the sodium-myo-inositol co-transporter-1 (SMIT1), a member of the sodium-glucose co-transporter (SGLT) family expressed in the heart. While myo-inositol is essential for phosphoinositide signaling, osmoregulation, and metabolic homeostasis, dysregulation of SMIT1-mediated myo-inositol transport may contribute to key pathological mechanisms in HF. This study aims to elucidate the role of SMIT1 in the failing heart, especially during left ventricular remodeling that precedes it. Methods and resultsWe used a mouse model of pressure overload induced by transverse aortic constriction in wild-type (WT) mice and mice lacking SMIT1 (Smit1-/-), and primary cultured cardiomyocytes. By combining molecular, structural and functional studies, RNA-sequencing, and calcium measurements, we demonstrate the contribution of myo-inositol and SMIT1 to pathological hypertrophy and the progression towards HF. We found that in comparison to WT controls, Smit1-/- mice were protected against aortic banding induced systolic dysfunction, cardiac fibrosis and hypertrophy. This hypertrophic response was driven by SMIT1 expression in cardiomyocytes, where it favors intracellular myo-inositol and Na+ entry, leading to inositol 1,4,5-trisphosphate (IP3)- and Ca2+-dependent pro-hypertrophic signaling. Following hemodynamic stress, deletion of SMIT1 significantly altered IP3/calcium effectors, including Carabin, which modulates cardiac hypertrophy through inhibition of the calcineurin/NFAT and Ras/ERK1/2 pathways. ConclusionsThis work provides important insights into the role of myo-inositol and SMIT1 in cardiomyocytes. We demonstrate that SMIT1 is a key driver of pathological hypertrophy by inducing an IP3/Ca2+-dependent pro-hypertrophic transcriptional reprogramming in cardiomyocytes. These findings identify SMIT1 as a promising therapeutic target for preventing or treating pathological cardiac hypertrophy and HF.

cell biology↗