image: (A) Representative M-mode echocardiography of short axis and representative PW-mode echocardiography of four-chamber section. (B) Left ventricular ejection fraction (EF%). (C) Left ventricular fractional shortening (FS%). (D) Left ventricular isovolumic relaxation time (IVRT). (E) E peak. (F) A peak. (G) E/A. n = 4; ∗P < 0.05; ∗∗P < 0.01.
Credit: Min Luo, Lingjuan Liu, Wenjing Yuan, Junjun Quan, Mi Li, Jie Tian
This new study published in Genes & Diseases by researchers from Children’s Hospital of Chongqing Medical University uncovers a previously underappreciated metabolic shift in a cTnIR193H transgenic mouse model, demonstrating that early-stage diastolic dysfunction is associated with enhanced glucose uptake and oxidation mediated by PI3K/Akt signaling.
Using a transgenic cTnI193His-M mouse model, the researchers performed longitudinal echocardiographic assessment and identified the onset of diastolic dysfunction at four months of age, marked by prolonged isovolumic relaxation time and altered E/A ratio. Despite preserved or even elevated systolic indices, these mice exhibited significantly increased myocardial ATP content, ATPase activity, and mitochondrial number, indicating a state of heightened energy metabolism.
To determine the substrate source underlying this metabolic state, the researchers analyzed key transporters mediating fatty acid and glucose uptake. While expression of the fatty acid transporter CD36 decreased, the glucose transporter GLUT4 was significantly upregulated at both mRNA and protein levels, with increased membrane localization. Proteomic profiling further revealed enrichment of glycolysis/gluconeogenesis pathways, and biochemical assays confirmed elevated cardiac glucose content without corresponding increases in lactate, suggesting preferential glucose oxidation rather than anaerobic glycolysis.
Phosphoproteomic analysis provided mechanistic insight into this metabolic reprogramming. The inositol phosphate metabolism pathway and PI3K/Akt signaling were significantly enriched. Western blot analysis demonstrated increased PI3K expression and elevated Akt phosphorylation in mutant hearts. In primary cardiomyocytes expressing cTnIR193H, pharmacologic inhibition of PI3K with LY294002 attenuated Akt activation and reduced glucose uptake, confirming a causal role for PI3K/Akt signaling in driving GLUT4-mediated glucose transport.
However, prolonged reliance on glucose metabolism was associated with increased oxidative stress. Mutant cardiomyocytes exhibited elevated malondialdehyde levels and reduced superoxide dismutase activity, indicating lipid peroxidation and impaired antioxidant defense. These findings suggest that early compensatory metabolic adaptation may predispose to later myocardial injury, fibrosis, and heart failure progression.
Collectively, this study establishes that cTnIR193H-induced RCM is accompanied by PI3K/Akt-dependent metabolic remodeling toward enhanced glucose utilization during early diastolic dysfunction. By linking sarcomeric mutation to substrate reprogramming and oxidative stress, the study provides new insight into metabolic contributions to restrictive cardiomyopathy and highlights the PI3K/Akt–GLUT4 axis as a potential therapeutic target for preventing advanced heart failure in cTnI mutation-associated RCM.
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