Lopaschuk, G. D. | Search bioRxiv

bioRxiv2024

Sarcomeric SRX:DRX Equilibrium in Alport and LDLR/P407 Mouse Models of HFpEF.

Cardiac myosin energetic states that regulate heart contractility define interactions of myosin cross-bridges with actin-containing thin filaments have been functionally linked with the pathology of hypertrophic cardiomyopathy (HCM). In particular, the balance between the disordered relaxed (DRX) and super relaxed (SRX) states that correlate respectively with enhanced force and energy conservation significantly determine myocardial performance and energy utilization. Compelling evidence suggests that a balanced SRX and DRX states proportion is a prerequisite for long-term cardiac health. Whereas roles for altered SRX: DRX proportions in HCM have been studied in depth, the mechanics of sarcomeric dysfunction and SRX: DRX proportions have not been reported in models of acquired heart failure (HF) including HF with preserved ejection fraction (HFpEF). Here, we quantified SRX andDRX myosin populations in two mouse models of HFpEF, including Alport and LDLR/P407 mice that represent cardiorenal/hypertensive and cardiometabolic/hyperlipidemic mouse models of HFpEF, respectively. We report significant changes in the SRX:DRX in both HFpEF mouse models, with an increased DRX state associated with Alport mice and a stabilized SRX state associated with LDLR/P407 mice. These findings correlate respectively with the hypercontractility and metabolic dysregulation with bradycardia phenotypes.

cell biology↗

bioRxiv2023

Loss of Skeletal Muscle Pyruvate Dehydrogenase Induces Lactic Acidosis and Adaptive Anaplerotic Compensation via Pyruvate-Alanine Cycling and Glutaminolysis

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the TCA cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes the early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders. HighlightsO_LISkeletal Muscle PDH is essential for survival C_LIO_LILoss of muscle PDH induces lactic acidosis and premature death C_LIO_LILoss of muscle PDH enhances pyruvate transformations and glutaminolysis C_LIO_LIHigh-fat diet supplementation abolishes early mortality and overt phenotype induced by muscle PDH loss C_LI

cell biology↗