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bioRxiv · 10.1101/2025.08.13.670184

Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy

Schmidt, A. V.·Thambadurai, T.·D'annibale, O.·Bharathi, S.·Wood, T.·Goetzman, E. S.·Stelzer, J. E.
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Abstract

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall, and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). Development of therapies to increase and enhance LFCA FAO are underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Myosin binding protein-C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation, but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3-/- mice, and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle.

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Schmidt, A. V., Thambadurai, T., D'annibale, O., Bharathi, S., Wood, T., Goetzman, E. S., Stelzer, J. E.. 2025-08-18. Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy. https://doi.org/10.1101/2025.08.13.670184

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