Biology subjects

Balse, E.

Publications and source records attributed to Balse, E..

8 recordsLinked to original sources

bioRxiv2026

Maternal obesity accelerates cardiomyocyte maturation and programs adult heart dysfunction in offspring

Rationale: Maternal obesity increases cardiovascular risk in offspring, but the developmental mechanisms linking early-life metabolic stress to adult heart dysfunction remain poorly understood, and whether maternal obesity alters the postnatal maturation of the cardiomyocyte itself has not been addressed. Objective: To determine whether maternal high-fat diet alters the developmental trajectory of postnatal cardiomyocyte maturation and its functional consequences in adult offspring. Methods: In a rat model of maternal high-fat diet, longitudinal echocardiographic and invasive hemodynamic phenotyping were combined with transcriptomic, lipidomic, and ultrastructural analyses across four postnatal stages. Results: Offspring exposed to maternal high-fat diet displayed accelerated postnatal cardiac maturation, with premature activation of contractile, calcium-handling and metabolic gene programs, concentric hypertrophy, and enhanced systolic performance in juvenile life. This precocious maturation was not sustained: by adulthood, ejection fraction and intrinsic myocardial contractility progressively declined, coinciding with disorganization of sarcomeres, intercalated discs, and excitation-contraction coupling proteins, in the absence of fibrosis, lipid accumulation or major mitochondrial respiratory dysfunction. Conclusions: These findings reveal accelerated cardiomyocyte maturation as a developmental mechanism linking maternal obesity to long-term cardiac vulnerability, with cardiomyocyte cytoarchitecture disruption emerging as an early hallmark that precedes overt systolic failure. Key words: Maternal obesity, DOHaD, postnatal cardiac maturation, cardiomyocyte cytoarchitecture, systolic dysfunction

pathology↗

bioRxiv2024

Depleting trafficking regulator CASK promotes intercalated disc organization and ventricular function

BackgroundThe intercalated disc (ID) electromechanically couples adjacent cardiomyocytes. Alteration of this structure plays a central role in cardiac arrhythmias, notably arrhythmogenic cardiomyopathy (ACM), an inherited genetic disorder of desmosomes. Calcium/Calmodulin-Dependent Serine Protein Kinase (CASK), a costameric component of the lateral membrane, regulates cardiomyocyte protein trafficking. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts. MethodsWe studied the outcomes of CASK depletion in neonatal rat hearts using a cardiac-specific adeno-associated virus strategy. We used conventional and strain echocardiography, hemodynamics, electrocardiography, histology, and gene and protein expression studies to characterize adult rat hearts. We also studied the effects of CASK depletion in neonatal rat ventricular cardiomyocytes (NRVM), and control and ACM (PKP2+/-) IPS cell-derived CM (hIPS-CM) using proteomics, electron microscopy, high-resolution imaging, mechano-scanning ion conductance microscopy (mechano-SICM), and stress resistance tests. We studied cardiac CASK expression and localization in human ACM and non-transplantable control hearts. ResultsDepletion of CASK in our multiple experimental models revealed that CASK regulates cardiomyocyte IDs. In rats, CASK depletion improved contractile reserve and compliance. In cultured rat cardiomyocytes, CASK knockdown increased localization of connexin 43 (Cx43) and PKP2 at IDs, resulting in increased contact stiffness. In PKP2+/- hIPS-CMs, CASK expression was increased. CASK depletion in these cells promoted PKP2 accumulation at cell contacts, formation of desmosome-like structures, and stress resistance. In the right ventricles of ACM patients, CASK protein level was also increased and CASK abnormally localized at the ID. ConclusionCASK functions as a repressor of ID organization and tissue cohesion, suggesting novel mechanisms for regulating ID structure and function. These observations, along with CASK upregulation and mislocalization in ACM, open up new perspectives on understanding the pathophysiology of ACM and suggest innovative strategies for its treatment.

physiology↗

bioRxiv2024

Inhibition of Atrial Natriuretic Peptide Clearance Reduces Myocardial Fibrosis and Improves Cardiac Function in Diabetic Rats

BackgroundNatriuretic peptides (NP) exert pleotropic effects through the recruitment of cGMP-signaling pathways depending on their bioavailability which is regulated by clearance receptors and peptidases. Here, we tested the hypothesis that increasing myocardial bioavailability of NP has a beneficial effect on heart failure. We studied the effects of a mutated NP, MANP, resistant to neprilysin in a model of diabetic cardiomyopathy characterized by a marked myocardial fibrosis. MethodsNatriuretic peptides as well as sacubritril were delivered via osmotic mini-pumps to high-fat/streptozotocin-induced type-2 diabetic (T2D) rats. Cardiac function was evaluated by echocardiography. Myocardial remodeling was studied by histological approaches, collagen phenotype and measurement of cGMP tissue concentration. Live-cell cGMP biosensing was conducted on cultured rat cardiac fibroblasts to investigate biological effects of NPs. cGMP signaling pathway was studied using various antibody arrays and biochemicals assays in cardiac tissue and cultured fibroblasts. ResultsMANP exhibits superior efficacy than ANP in reducing left ventricular dysfunction and to reduce myocardial fibrosis with less extracellular matrix deposition. In vitro, MANP and ANP similarly generated cGMP and activated PKG signaling pathway in cardiac fibroblasts, attenuating SMAD activation, collagen secretion and cell proliferation. Nevertheless, in vivo, MANP enhanced cardiac cGMP accumulation and was more potent than ANP in activating myocardial cGMP/PKG signaling and inhibiting the profibrotic SMAD pathway. Endopeptidase inhibition using sacubitril also led to cardiac cGMP accumulation and reduced myocardial fibrosis ConclusionsMyocardial bioavailability of ANP is a major determinant of peptide efficacy in reducing cardiac fibrosis and improving pump function during diabetic cardiomyopathy. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIMutated atrial natriuretic peptide (MANP) resistant to neprilysin degradation outperforms wild-type ANP in reducing myocardial fibrosis and improving cardiac function in type-2 diabetes (T2D) C_LIO_LIWhile the antifibrotic effect of the two ANP isoforms involves similarly cGMP-dependent PKG signaling and inhibition of fibroblast activation, MANP enhanced cGMP myocardial concentration more importantly than ANP. C_LIO_LISacubitril that inhibits ANP degradation also reduces cardiac fibrosis through myocardial accumulation of cGMP and activation of cGMP-dependent PKG signaling pathway. C_LIO_LICardiac bioavailability of natriuretic peptides is a major determinant of their effects on myocardial fibrosis and cardiac function. C_LI What Are the Clinical Implications?O_LIMyocardial bioavailability of natriuretic peptides is crucial for mitigating cardiac fibrosis and improving cardiac function in diabetic cardiomyopathy and heart failure in general. C_LIO_LIMANP holds the potential as a new treatment modality in the management of heart failure. C_LI

physiology↗

bioRxiv2020

HIGH FAT DIET STIMULATES BETA-OXIDATION, ALTERS ELECTRICAL PROPERTIES AND INDUCES ADIPOGENICITY OF ATRIA IN OBESE MICE

Metabolic disorders such as obesity are risk factors of atrial fibrillation, not only by sharing comorbidities but likely through their direct impact on atria, notably its adipogenicity. Here, we submitted mice that lack cardiac adipose tissue to a high fat diet and first studied the atrial metabolomic and lipidomic phenotypes using liquid chromatography-mass spectrometry. We found an increased consumption of free fatty acid by the beta-oxidation and an accumulation of long-chain lipids in atria of obese mice. Free fatty acid was the main substrate of mitochondrial respiration studied in the saponin-permeabilized atrial muscle. Conducted action potential recorded in atrial trabeculae was short, and ATP-sensitive potassium current was increased in perforated patch-clamp atrial myocytes of obese mice. There was histological and phenotypical evidence for an accumulation of adipose tissue in obese mice atria. Thus, an obesogenic diet transforms the energy metabolism, causes fat accumulation and induces electrical remodeling of atria myocardium. HIGHLIGHTS- Untargeted metabolomic and lipidomic analysis revealed that a high fat diet induces profound transformation of atrial energy metabolism with beta-oxidation activation and long-chain lipid accumulation. - Mitochondria respiration studied in atrial myocardial trabecula preferentially used Palmitoyl-CoA as energy substrate in obese mice. - Atria of obese mice become vulnerable to atrial fibrillation and show short action potential due to the activation of K-ATP dependent potassium current. - Adipocytes and fat molecular markers were detected in atria of obese mice together with an inflammatory profile consistence with a myocardial accumulation of fat.

physiology↗

bioRxiv2020

Repression of Pdzrn3 is required for heart maturation and protects against heart failure

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

physiology↗

bioRxiv2019

Distinct CASK domains control cardiac sodium channel membrane expression and focal adhesion anchoring

Membrane-associated guanylate kinase (MAGUK) proteins function as adaptor proteins to mediate the recruitment and scaffolding of ion channels in the plasma membrane in various cell types. In the heart, the protein CASK (Calcium/CAlmodulin-dependent Serine protein Kinase) negatively regulates the main cardiac sodium channel, NaV1.5, which carries the sodium current (INa) by preventing its anterograde trafficking. CASK is also a new member of the dystrophin-glycoprotein complex, and like syntrophin, binds to the C-terminal domain of the channel. Here we show that both L27B and GUK domains are required for the negative regulatory effect of CASK on INa and NaV1.5 surface expression and that the HOOK domain is essential for interaction with the cell adhesion dystrophin-glycoprotein complex. Thus, the multi-modular structure of CASK potentially provides the ability to control channel delivery at adhesion points in cardiomyocyte.\n\nSUMMARYSequential functional domain deletion approach identifies three critical domains of CASK in cardiomyocytes. CASK binds the cell adhesion dystrophin-glycoprotein complex through HOOK domain and inhibits NaV1.5 channel membrane expression by impeding trafficking through L27B and GUK domains.

physiology↗

bioRxiv2019

Microtubule polymerization state and clathrin-dependent internalization regulate dynamics of cardiac potassium channel

Ion channel trafficking powerfully influences cardiac electrical activity as it regulates the number of available channels at the plasma membrane. Studies have largely focused on identifying the molecular determinants of the trafficking of the atria-specific KV1.5 channel, the molecular basis of the ultra-rapid delayed rectifier current IKur. Besides, regulated KV1.5 channel recycling upon changes in homeostatic state and mechanical constraints in native cardiomyocytes has been well documented. Here, using cutting-edge imaging in live myocytes, we investigated the dynamics of this channel in the plasma membrane. We demonstrate that the clathrin pathway is a major regulator of the functional expression of KV1.5 channels in atrial myocytes, with the microtubule network as the prominent organizer of KV1.5 transport within the membrane. Both clathrin blockade and microtubule disruption result in channel clusturization with reduced membrane mobility and internalization, whereas disassembly of the actin cytoskeleton does not. Mobile KV1.5 channels are associated with the microtubule plus-end tracking protein EB1 whereas static KV1.5 clusters are associated with stable acetylated microtubules. In human biopsies from patients in atrial fibrillation associated with atrial remodeling, drastic modifications in the trafficking balance occurs together with alteration in microtubule polymerization state resulting in modest reduced endocytosis and increased recycling. Consequently, hallmark of atrial KV1.5 dynamics within the membrane is clathrin- and microtubule-dependent. During atrial remodeling, predominance of anterograde trafficking activity over retrograde trafficking could result in accumulation ok KV1.5 channels in the plasma membrane.

cell biology↗

bioRxiv2019

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause the accumulation of lipids in lysosome compartment. However, the full nature of lipids accumulating in lysosomes and the physiological consequences of such accumulation are not known. Here we show that loss of spatacsin, but also downregulation of clathrin, inhibited the formation of tubules on late endosomes/lysosomes and prevented the clearance of cholesterol from this subcellular compartment. Using spatacsin-deficient cells, we evaluated the consequences of impaired cholesterol clearance from late endosomes/lysosomes. The accumulation of cholesterol in late endosomes/lysosomes led to lower cholesterol levels in the plasma membrane, enhancing the entry of extracellular calcium by store-operated calcium entry and increasing resting cytosolic calcium levels. Higher cytosolic calcium levels promoted the nuclear translocation of the master regulator of lysosomes TFEB. Downregulation of TFEB or decrease in resting calcium levels in absence of spatacsin partially corrected the formation of tubules and the accumulation of cholesterol in lysosomes, suggesting that spatacsin could be indirectly implicated in the formation of tubules. Our work reveals a homeostatic balance between cholesterol trafficking and cytosolic calcium levels and shows that loss of spatacsin impairs this homeostatic equilibrium.

cell biology↗