Exercise Training Reverses Lipotoxicity-induced Cardiomyopathy by Inhibiting HMGCS2

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Exercise Physiology

Background:

• Lipotoxic cardiomyopathy results from lipid metabolic disorders, leading to cardiac hypertrophy and fibrosis.
• The role of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and miR-344g-5p in exercise-mediated cardioprotection against lipotoxicity is not fully understood.

Purpose of the Study:

• To determine the effect of exercise training on preventing lipotoxic cardiomyopathy.
• To investigate the molecular mechanisms involving HMGCS2 and miR-344g-5p in cardiomyocytes during exercise.

Main Methods:

• Male C57BL/6 mice were subjected to a high-fat diet (HFD) followed by swimming exercise or sedentary conditions.
• Cardiac function was assessed, and molecular analyses were performed on heart tissue and plasma.
• In vitro studies utilized palmitate-induced neonatal mouse cardiomyocytes treated with Hmgcs2 siRNA or miR-344g-5p mimics.

Main Results:

• HFD induced cardiac hypertrophy, fibrosis, and reduced cardiac function, which were attenuated by exercise.
• Exercise increased HMGCS2 and miR-344g-5p expression while decreasing junctophilin-2 (JPH2) levels in HFD mice.
• In cardiomyocytes, HMGCS2 silencing or miR-344g-5p overexpression reduced apoptosis and caspase-3 cleavage and increased JPH2 expression.

Conclusions:

• Exercise training effectively prevents lipotoxic cardiomyopathy by mitigating lipid metabolic disorders, cardiac hypertrophy, and fibrosis.
• Exercise-mediated cardioprotection is achieved by upregulating miR-344g-5p, which targets HMGCS2 mRNA, thereby inhibiting HMGCS2 upregulation and subsequent lipotoxicity.