Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Abstract

The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) pump is responsible for regulating calcium (Ca 2+ ) within myocytes, with SERCA2a being the dominant isoform in cardiomyocytes.Its inhibitor, phospholamban (PLN), acts by decreasing the affinity of SERCA for Ca 2+ . Changes in the SERCA2a:PLN ratio can cause Ca 2+ dysregulation often seen in patients with dilated cardiomyopathy and heart failure. The enzyme glycogen synthase kinase-3 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low-dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wildtype C57BL/6J mice were fed low-dose lithium via drinking water (10 mg kg −1 day −1 LiCl for 6 weeks) and left ventricles were harvested. GSK3 activity was significantly reduced in LiClfed versus control-fed mice. The apparent affinity of SERCA for Ca 2+ was also increased (pCa 50 ; control, 6.09 ± 0.03 versus LiCl, 6.26 ± 0.04, P < 0.0001) along with a 2.0-fold increase in SERCA2a:PLN ratio in LiCl-fed versus control-fed mice. These findings suggest that low-dose lithium supplementation can improve SERCA function by increasing the SERCA2a:PLN ratio.Future studies in murine preclinical models will determine whether GSK3 inhibition via low-dose lithium could be a potential therapeutic strategy for dilated cardiomyopathy and heart failure. K E Y W O R D Scalcium, cardiac muscle, GSK3, lithium supplementation, phospholamban, SERCA 1 wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:666-675.

Neuronatin regulates whole‐body metabolism: is thermogenesis involved?

“…11,[47][48][49] Thus, finding ways to reduce the amount of PLN relative to SERCA is an active field of research. 50,51 Long considered to be the functional homolog of PLN, sarcolipin (SLN) is a small 31 amino acid protein that binds to and regulates the SERCA pump. 52,53 Like PLN, SLN can reduce SERCA's affinity for Ca 2+ .…”

“…Western blotting and co-immunoprecipitation protocols were performed as previously described using 4%-15% TGX precast gels (Bio-Rad Laboratories) and PVDF membranes. 50,[60][61][62] Primary antibodies for NNAT were obtained from ProteinTech (26905-1-AP), whereas SERCA1a (MA3-912) and SERCA2a (MA3-919) were obtained from ThermoFisher…”

“…Overexpression of PLN and increases in the ratio of PLN relative to SERCA has been implicated in dilated cardiomyopathy, heart failure, and skeletal muscle myopathies 11,47–49 . Thus, finding ways to reduce the amount of PLN relative to SERCA is an active field of research 50,51 …”

“…Mice were fed a standard chow diet and housed under 12 h light:dark periods; and all animal protocols were approved by the Brock University Animal Care Committee. Western blotting and co‐immunoprecipitation protocols were performed as previously described using 4%‐15% TGX precast gels (Bio‐Rad Laboratories) and PVDF membranes 50,60–62 . Primary antibodies for NNAT were obtained from ProteinTech (26905‐1‐AP), whereas SERCA1a (MA3‐912) and SERCA2a (MA3‐919) were obtained from ThermoFisher…”

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

“…Recently, Wang X et al demonstrated that lithium induces upregulation of ITCH and promotes ubiquitylation and degradation of Gli1, a regulator of the Hedgehog signaling pathway, in PANC-1 cells [ 229 ]. A recent report demonstrated that low-dose lithium feeding increases sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) to phospholamban ratio and improved SERCA function in the murine left ventricle [ 230 ], suggesting a protective role in the heart. Although the precise mechanism by which lithium upregulates ITCH is unclear, there is a possibility that ITCH target therapy is beneficial in the heart.…”