Low-dose lithium chloride supplementation protects cardiac SERCA function during heat stress

Background: The sarco(endo)plasmic reticulum calcium (Ca 2+ )-ATPase (SERCA) is responsible for ~70% of intracellular Ca 2+ removal in cardiac muscle contributing to the regulation of cardiac relaxation and contractility. SERCA is susceptible to heightened oxidative stress that is often observed with aging and disease resulting in reduced activity and cardiac dysfunction. Under normal physiological conditions, the inhibition of the enzyme glycogen synthase kinase 3 (GSK3) via low-dose lithium chloride (LiCl) supplementation (10 mg/kg/day) improved SERCA function in murine cardiac muscle via an increase in SERCA and decrease in its regulator, phospholamban. However, GSK3 also represses the transcription of the heat shock protein 70 (Hsp70), which can bind to SERCA and protect it from oxidative damage. Here, we sought to determine whether lithium treatment could protect murine cardiac SERCA function against heat stress by increasing Hsp70 content. Methods: Young (3-6 month old) male C57BL6 mice were provided water with or without low-dose (10 mg/kg/day) LiCl for 6-12 weeks ad libitum. High frequency ultrasound was done to assess cardiac morphology and contractility. Left ventricles (LV) were collected and SERCA activity assays were performed at baseline, and 30 and 60 min after heat treatment (40˚C incubation). Western blots were performed on non-heated and heated (60 min) samples for SERCA2, PLN, Hsp70 and GSK3 phosphorylation status. Results: Assessment of cardiac function indicated functional eccentric hypertrophy after 12 weeks of LiCl treatment with greater LV internal diameter during systole and diastole (Ctrl vs LiCl: 2.74 vs. 2.99mm, p<0.05; 3.99 vs. 4.32mm, p<0.01, respectively) as well as increases in end-diastolic volume and stroke volume (Ctrl vs LiCl: 70.1 vs. 84.4μL, p<0.05; 41.8 vs 49.1μL, p<0.05, respectively). This was associated with an increase in Ser9 inhibitory phosphorylation of GSK3β in the LiCl-treated mice. With respect to SERCA, after 6 weeks of treatment, LiCl mitigated reductions in absolute maximal SERCA activity at 30 and 60 minutes of heat stress (Ctrl vs LiCl: 46.2% vs 66.4% and 30.6% vs 43%, respectively; p<0.05). However, markers of oxidative stress (protein nitration and nitrosylation) and Hsp70 levels were not different between control and LiCl hearts. Conclusions: Low-dose LiCl supplementation can improve cardiac function potentially through its improvements in SERCA function in both physiological and heat stress conditions. The exact mechanisms leading to the apparent protection against heat stress are still under investigation, with future directions including measurements of total and oxidized glutathione levels. SIH holds a Vanier Canada Graduate Scholarship. VAF is a Tier 2 Canada Research Chair in Muscle Plasticity and Tissue-Remodelling. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.