Ketogenic diet regulates cardiac remodeling and calcium homeostasis in diabetic cardiomyopathy

Abstract Background Ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis depend on the homeostasis of calcium (Ca²⁺). We investigated the effects of KD on Ca²⁺ homeostasis and electrophysiology in diabetic cardiomyopathy. Methods Male Wistar rats were created to have diabetes mellitus (DM) by applying streptozotocin (65 mg/kg intraperitoneally), and they were treated for 6 weeks with a normal diet (ND) or KD. Our electrophysiological and Western blot analyses assessed myocardial Ca²⁺ homeostasis in ventricular preparations in vivo. Results Unlike those on KD, DM rats treated with ND exhibited a prolonged QTc interval and action potential duration. Compared to control and DM rats on KD, DM rats treated with ND also showed lower intracellular Ca²⁺ transients, sarcoplasmic reticular Ca²⁺ content, sodium (Na⁺)-Ca²⁺exchanger currents (reverse mode), L-type Ca²⁺ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents, phosphorylated phospholamban/phospholamban ratios, and phosphorylated ryanodine receptor 2 (RyR2) at serine 2808/RyR2 ratios but higher Ca²⁺/calmodulin-dependent protein kinase II (CaMKII-δ) levels. Moreover, DM rats treated with ND demonstrated a higher frequency and incidence of Ca²⁺ leak, mitochondrial and cytosolic reactive oxygen species, Na⁺/hydrogen-exchanger currents, and late Na⁺ currents than control and DM rats on KD. Conclusion KD treatment may attenuate the effects of DM-dysregulated Na⁺ and Ca²⁺ homeostasis, contributing to its cardioprotection in DM.