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New Findings: What is the central question of this study? Inhibition of glycogen synthase kinase-3 (GSK3) has been shown to improve cardiac SERCA2a function. Lithium can inhibit GSK3, but therapeutic doses used in treating bipolar disorder can have toxic effects. It has not been determined whether subtherapeutic doses of lithium can improve cardiac SERCA function. What is the main finding and its importance? Using left ventricles from wild-type mice, we found that subtherapeutic lithium feeding for 6 weeks decreased GSK3 activity and increased cardiac SERCA function compared with control-fed mice. These findings warrant the investigation of low-dose lithium feeding in preclinical models of cardiomyopathy and heart failure to determine the therapeutic benefit of GSK3 inhibition.

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 wild-type 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 LiCl-fed 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.

Titel:	Low-dose lithium feeding increases the SERCA2a-to-phospholamban ratio, improving SERCA function in murine left ventricles.
Autor/in / Beteiligte Person:	Hamstra, SI ; Kurgan, N ; Baranowski, RW ; Qiu, L ; Watson, CJF ; Messner, HN ; MacPherson, REK ; MacNeil, AJ ; Roy, BD ; Fajardo, VA
Link:	Full Text Finder (Volltext)
Zeitschrift:	Experimental physiology, Jg. 105 (2020-04-01), Heft 4, S. 666-675
Veröffentlichung:	Cambridge, Eng : Wiley-Blackwell ; <i>Original Publication</i>: Cambridge ; New York, NY, USA : Published for the Physiological Society by Cambridge University Press, c1990-, 2020
Medientyp:	academicJournal
ISSN:	1469-445X (electronic)
DOI:	10.1113/EP088061
Schlagwort:	Animals Calcium metabolism Cardiomyopathies metabolism Glycogen Synthase Kinase 3 metabolism Heart Failure metabolism Heart Ventricles metabolism Male Mice Mice, Inbred C57BL Muscle Proteins metabolism Myocytes, Cardiac drug effects Myocytes, Cardiac metabolism Phosphorylation drug effects Calcium-Binding Proteins metabolism Heart Ventricles drug effects Lithium pharmacology Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Exp Physiol] 2020 Apr; Vol. 105 (4), pp. 666-675. <i>Date of Electronic Publication: </i>2020 Mar 18. MeSH Terms: Calcium-Binding Proteins / metabolism ; Heart Ventricles / drug effects ; Lithium / pharmacology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism ; Animals ; Calcium / metabolism ; Cardiomyopathies / metabolism ; Glycogen Synthase Kinase 3 / metabolism ; Heart Failure / metabolism ; Heart Ventricles / metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Proteins / metabolism ; Myocytes, Cardiac / drug effects ; Myocytes, Cardiac / metabolism ; Phosphorylation / drug effects References: Asahi, M., Nakayama, H., Tada, M., & Otsu, K. (2003). Regulation of sarco(endo)plasmic reticulum Ca2+ adenosine triphosphatase by phospholamban and sarcolipin: Implication for cardiac hypertrophy and failure. 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Grant Information: 05833 International Natural Sciences and Engineering Research Council of Canada; International NSERC Doctoral Award; International NSERC Undergraduate Student Research Award; International Brock University Explore Grant Contributed Indexing: Keywords: GSK3; SERCA; calcium; cardiac muscle; lithium supplementation; phospholamban Substance Nomenclature: 0 (Calcium-Binding Proteins) ; 0 (Muscle Proteins) ; 0 (phospholamban) ; 9FN79X2M3F (Lithium) ; EC 2.7.11.26 (Glycogen Synthase Kinase 3) ; EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) ; EC 7.2.2.10 (Atp2a2 protein, mouse) ; SY7Q814VUP (Calcium) Entry Date(s): Date Created: 20200223 Date Completed: 20210819 Latest Revision: 20210819 Update Code: 20240513

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