Exercise Training Reverses Lipotoxicity-induced Cardiomyopathy by Inhibiting HMGCS2

Abstract

Purpose This study aimed to determine the effect of exercise training on preventing lipotoxic cardiomyopathy and to investigate the role of the 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and miR-344g-5p in cardiomyocytes. Methods Male C57BL/6 mice were fed a 60% high-fat diet (HFD) for 12 wk then began swimming exercise or remained sedentary for 8 wk. Thereafter, cardiac function was assessed by echocardiography, and heart tissue and plasma were collected for further measurements. The molecular mechanism of exercise was investigated after treating Hmgcs2 siRNA in palmitate-induced neonatal mouse cardiomyocytes. Results HFD induced myocardial hypertrophy and fibrosis and reduced coronary reserve and cardiac function. HMGCS2 levels increased, but junctophilin-2 (JPH2) levels decreased in HFD mice hearts. Such effects were attenuated by swimming exercise. Mechanistically, Hmgcs2 silencing prevented apoptosis and caspase-3 cleavage and elevated the expression of JPH2 in palmitate-stimulated cardiomyocytes. In addition, exercise promoted miR-344g-5p expression in HFD hearts. The overexpression of miR-344g-5p by chemical mimic reduced HMGCS2, apoptosis, and caspase-3 cleavage and elevated JPH2 expression in palmitate-induced cardiomyocytes. Conclusion Our results suggest that exercise limits lipid metabolic disorder, cardiac hypertrophy, and fibrosis and aids in the prevention of lipotoxic cardiomyopathy. Exercise-mediated cardioprotection by upregulating miR-344g-5p, which targets Hmgcs2 mRNA, prohibits HMGCS2 upregulation and thus lipotoxicity.

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats

“…Myocardial Hmgcs2 is the rate-limiting enzyme of ketone body production, which promotes the generation of 3-hydroxybutyric acid in the myocardium. However, study has shown that the Hmgcs2 overexpression is related to myocardial lipotoxicity caused by a high-fat diet in mice, and the inhibition of the upregulation of Hmgcs2 can reverse cardiomyopathy induced by lipotoxicity ( Sikder et al, 2018 ; Li et al, 2021 ). Thus, the cardioprotective effect of SGLT2i may not be mediated by upregulation of Hmgcs2 protein.…”

The role of junctophilin proteins in cellular function

“…Reduced JPH2 expression levels have also been reported in a mouse model of lipotoxic cardiomyopathy. Male C57BL/6 mice that were fed a 60% high-fat diet for 12 wk developed myocardial hypertrophy, fibrosis, reduced coronary reserve, and suppressed cardiac function ( 253 ). The reduced JPH2 expression levels could be reversed by swimming exercise and silencing of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), suggesting that the cardiomyopathy development itself led to loss of JPH2.…”

HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress

“…HMGCS2 is a key enzyme that controls ketone synthesis [ 35 ]. Expression and activity of HMGCS2 are regulated by several transcription factors and by posttranslational modifications including acetylation [ 36 ].…”

“…In addition, HMGCS2 was also elevated heart tissues from streptozotocin-induced diabetic rat [ 38 ]. Li et al showed that exercise training could reverse lipotoxicity-induced cardiomyopathy by repressing HMGCS2 [ 35 ]. Wang et al demonstrated that silencing of peroxisome proliferator-activated receptor-alpha alleviated myocardial injury in DCM by repressing HMGCS2 expression [ 39 ].…”