Relative contributions of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction.

Labbe, E.-A.; Thibodeau, S.-E.; Walsh-Wilkinson, E.; Chalifour, M.; Sirois, P.-O.; Leblanc, J.; Arsenault, M.; Couet, J.

doi:10.1101/2025.02.03.636256

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.02.03.636256

Relative contributions of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction.

Labbe, E.-A.·Thibodeau, S.-E.·Walsh-Wilkinson, E.·Chalifour, M.·Sirois, P.-O.·Leblanc, J.·Arsenault, M.·Couet, J.

View original source ↗Export metadata ↓

Abstract

We recently proposed a new two-hit murine model of heart failure with preserved ejection fraction (HFpEF) amenable for both male and female animals. Using this model, we studied cardiac reverse remodelling (RR) after stopping the causing stress (Angiotensin II (AngII) + High-fat diet; MHS) after 28 days, and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. We showed this could lead to extensive cardiac left ventricle (LV) RR. Revisiting this HFpEF model, we studied the relative contribution to RR of correcting the diet and/or starting VE after stopping AngII. We also evaluate the extent of myocardial recovery after an extended period (12 weeks instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Discontinuing AngII but continuing the HFD blocked RR in females, not males. Removing AngII and correcting either the diet or implementing VE normalized most tested gene markers of LV hypertrophy or extracellular matrix, irrespective of sex. Twelve weeks of recovery was associated with normal LV morphology and function, except for abnormal diastolic echocardiographic parameters. A second MHS after these 12 weeks led to a loss of ejection fraction in males and LV dilatation. The response of females was like that after the first MHS, suggesting a better recovery. The MHS changed markers of myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity responsible for pyruvate entry in the mitochondria was reduced after MHS, and this was accompanied by an increase of PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR mostly normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining in males make them more sensitive to a second HFpEF-inducing stress.

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Labbe, E.-A., Thibodeau, S.-E., Walsh-Wilkinson, E., Chalifour, M., Sirois, P.-O., Leblanc, J., Arsenault, M., Couet, J.. 2025-02-08. Relative contributions of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction.. https://doi.org/10.1101/2025.02.03.636256

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

bioRxiv2026

Light-cycle time-restricted feeding remodels a hidden layer of the cardiac transcriptome through sex-specific transcript switching

Light-cycle time-restricted feeding disrupts daily cardiovascular and thermoregulatory rhythms, but the molecular effects of light-cycle time-restricted feeding on the heart have been measured only at the level of total gene expression. We used Oxford Nanopore long-read RNA sequencing to resolve the full-length ventricular transcriptome from male and female mice under ad libitum feeding or light-cycle time-restricted feeding across the 24-hour cycle. Greater than 20% of cardiac transcripts represent unannotated variants of known genes absent from the current GENCODE reference annotation. Light-cycle time-restricted feeding reorganizes transcript usage across hundreds of genes, including genes encoding splicing regulators, largely without changing total gene expression. The genes affected are sex-specific, with fewer than 2% of changes shared at the gene, transcript, and transcript-usage levels. We show that transcript-level regulation is a previously underrecognized component of the cardiac response to altered feeding behavior, undetected by conventional short-read approaches.

physiology↗