Effects of Low-Dose Lithium Supplementation on Thermal Inactivation of SERCA in Cardiac Muscle of Male Mice

The sarco(endo)plasmic reticulum calcium (Ca2+)-ATPase 2 (SERCA2) is a crucial regulator of cardiac muscle function that is sensitive to changes in the cellular environment, such as increased oxidative stress. This can be observed in heat stress experiments, where the thermal inactivation of SERCA is linked to an increased production of reactive oxygen species. Previous studies have shown that regulatory proteins, including phospholamban (PLN) and heat shock protein 70 (Hsp70), can physically bind to SERCA2, preserving its function in the face of heat stress. Furthermore, we have demonstrated that the inhibition of glycogen synthase kinase 3β (GSK3β) can alter the protein levels of PLN and HSP70 in cardiac tissues obtained from male mice; however, its potential downstream effects on the thermal inactivation of SERCA have not yet been investigated. In this study, we examined the potential effects of GSK3β inhibition through six weeks of low-dose lithium chloride supplementation (LiCl, 10 mg/kg body mass/day via drinking water) on the thermal inactivation of left ventricle SERCA2 obtained from male C57BL/6J mice. Our results show that LiCl supplementation increased inhibitory serine 9 phosphorylation on GSK3β while also significantly raising SERCA2 content and the SERCA2:PLN ratio. There were no changes to Hsp70 with LiCl supplementation. Although LiCl decreased baseline maximal SERCA activity, the decline in activity in response to heat stress was less compared to control. In conclusion, GSK3β inhibition with LiCl is associated with protection of SERCA from thermal inactivation in the heart, and future studies should explore the underlying cellular mechanisms.