Biology subjects

Guilbert, L.

Publications and source records attributed to Guilbert, L..

3 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↗

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↗

bioRxiv2021

Survey of peridomestic mammal susceptibility to SARS-CoV-2 infection

Wild animals have been implicated as the origin of SARS-CoV-2, but it is largely unknown how the virus affects most wildlife species and if wildlife could ultimately serve as a reservoir for maintaining the virus outside the human population. Here we show that several common peridomestic species, including deer mice, bushy-tailed woodrats, and striped skunks, are susceptible to infection and can shed the virus in respiratory secretions. In contrast, we demonstrate that cottontail rabbits, fox squirrels, Wyoming ground squirrels, black-tailed prairie dogs, house mice, and racoons are not susceptible to SARS-CoV-2 infection. Our work expands upon the existing knowledge base of susceptible species and provides evidence that human-wildlife interactions could result in continued transmission of SARS-CoV-2.

microbiology↗