Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca²⁺) homeostasis. We investigated the effects of a KD on Ca²⁺ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca²⁺ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an 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. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca²⁺ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca²⁺ leak, cytosolic reactive oxygen species, Na⁺/hydrogen-exchanger currents, and late Na⁺ currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na⁺ and Ca²⁺ homeostasis, contributing to its cardioprotection in DM.