{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T04:31:03Z","timestamp":1781152263209,"version":"3.54.1"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["05833"],"award-info":[{"award-number":["05833"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item>\n<jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Inhibition of glycogen synthase kinase\u20103 (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.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>Using left ventricles from wild\u2010type mice, we found that subtherapeutic lithium feeding for 6\u00a0weeks decreased GSK3 activity and increased cardiac SERCA function compared with control\u2010fed mice. These findings warrant the investigation of low\u2010dose lithium feeding in preclinical models of cardiomyopathy and heart failure to determine the therapeutic benefit of GSK3 inhibition.<\/jats:p>\n<\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The sarco(endo)plasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase (SERCA) pump is responsible for regulating calcium (Ca<jats:sup>2+<\/jats:sup>) within myocytes, with SERCA2a being the dominant isoform in cardiomyocytes. Its inhibitor, phospholamban (PLN), acts by decreasing the affinity of SERCA for Ca<jats:sup>2+<\/jats:sup>. Changes in the SERCA2a:PLN ratio can cause Ca<jats:sup>2+<\/jats:sup> dysregulation often seen in patients with dilated cardiomyopathy and heart failure. The enzyme glycogen synthase kinase\u20103 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low\u2010dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wild\u2010type C57BL\/6J mice were fed low\u2010dose lithium via drinking water (10\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0day<jats:sup>\u22121<\/jats:sup> LiCl for 6\u00a0weeks) and left ventricles were harvested. GSK3 activity was significantly reduced in LiCl\u2010fed <jats:italic>versus<\/jats:italic> control\u2010fed mice. The apparent affinity of SERCA for Ca<jats:sup>2+<\/jats:sup> was also increased (pCa<jats:sub>50<\/jats:sub>; control, 6.09\u00a0\u00b1\u00a00.03 <jats:italic>versus<\/jats:italic> LiCl, 6.26\u00a0\u00b1\u00a00.04, <jats:italic>P\u00a0<\/jats:italic>&lt;\u00a00.0001) along with a 2.0\u2010fold increase in SERCA2a:PLN ratio in LiCl\u2010fed <jats:italic>versus<\/jats:italic> control\u2010fed mice. These findings suggest that low\u2010dose 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\u2010dose lithium could be a potential therapeutic strategy for dilated cardiomyopathy and heart failure.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep088061","type":"journal-article","created":{"date-parts":[[2020,2,22]],"date-time":"2020-02-22T14:15:05Z","timestamp":1582380905000},"page":"666-675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Low\u2010dose lithium feeding increases the SERCA2a\u2010to\u2010phospholamban ratio, improving SERCA function in murine left ventricles"],"prefix":"10.1113","volume":"105","author":[{"given":"Sophie I.","family":"Hamstra","sequence":"first","affiliation":[{"name":"Department of Kinesiology Brock University  St. Catharines ON L2S 3A1 Canada"},{"name":"Centre for Bone and Muscle Health Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Kurgan","sequence":"additional","affiliation":[{"name":"Department of Kinesiology Brock University  St. Catharines ON L2S 3A1 Canada"},{"name":"Centre for Bone and Muscle Health Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan W.","family":"Baranowski","sequence":"additional","affiliation":[{"name":"Department of Kinesiology Brock University  St. Catharines ON L2S 3A1 Canada"},{"name":"Centre for Bone and Muscle Health Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colton J. F.","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holt N.","family":"Messner","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E. K.","family":"MacPherson","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"MacNeil","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Kinesiology Brock University  St. Catharines ON L2S 3A1 Canada"},{"name":"Centre for Bone and Muscle Health Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-3347","authenticated-orcid":false,"given":"Val A.","family":"Fajardo","sequence":"additional","affiliation":[{"name":"Department of Kinesiology Brock University  St. Catharines ON L2S 3A1 Canada"},{"name":"Centre for Bone and Muscle Health Brock University  St. Catharines ON L2S 3A1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(03)00037-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.83.12.1205"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2014.11.016"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.85923"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.08.020"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2010.09.004"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1079\/PNS19720062"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.020859"},{"key":"e_1_2_8_11_1","first-page":"4094","article-title":"Sarcolipin deletion in mdx mice impairs calcineurin signalling and worsens dystrophic pathology","volume":"27","author":"Fajardo V. A.","year":"2018","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170744"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-018-0687-7"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-013-6467-8"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3109\/07853890008998837"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2012.00014"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000018952.70505.F1"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-017-9998-2"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2004.52221.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118446"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09239-5"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.02.066"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1151"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38319"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61703-0"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nu.01.070181.002111"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401413200"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2012.07.005"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81662-1"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2018.09.002"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142267"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.32.19929"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015845"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)70790-2"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00736.2007"},{"issue":"1","key":"e_1_2_8_36_1","doi-asserted-by":"crossref","first-page":"S137","DOI":"10.1038\/sj.bjp.0707659","article-title":"Glycogen synthase kinase 3 (GSK3) in the heart: A point of integration in hypertrophic signalling and a therapeutic target? A critical analysis","volume":"153","author":"Sugden P. H.","year":"2008","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.04.022"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2005.06.033"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(69)90868-X"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(70)91446-7"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1139\/bcb-2014-0080"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FEP088061","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP088061","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/EP088061","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP088061","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T16:47:24Z","timestamp":1694018844000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/EP088061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,18]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1113\/EP088061"],"URL":"https:\/\/doi.org\/10.1113\/ep088061","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"value":"0958-0670","type":"print"},{"value":"1469-445X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,18]]},"assertion":[{"value":"2019-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}