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The Na,K\u2010ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that\n                      <jats:italic>ATP1A2<\/jats:italic>\n                      is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Mice heterozygous for the familial hemiplegic migraine type 2\u2013associated G301R mutation in the\n                      <jats:italic>Atp1a2<\/jats:italic>\n                      gene (\u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice) and matching wild\u2010type controls were compared. Reduced expression of the Na,K\u2010ATPase \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      isoform and increased expression of the \u03b1\n                      <jats:sub>1<\/jats:sub>\n                      isoform were observed in hearts from \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8\u2010month\u2010old \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3\u2010month\u2010old \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice were similar to wild\u2010type mice. Amplified Na,K\u2010ATPase\u2013dependent Src kinase\/Ras\/Erk1\/2 (p44\/42 mitogen\u2010activated protein kinase) signaling was observed in hearts from 8\u2010month\u2010old \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure\u2013associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5\u00b4,6,6\u00b4\u2010tetrachloro\u20101,1\u00b4,3,3\u00b4\u2010tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src\/Ras\/Erk1\/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8\u2010month\u2010old \u03b1\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>+\/G301R<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Our findings suggest that\n                      <jats:italic>ATP1A2<\/jats:italic>\n                      mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K\u2010ATPase\u2013dependent reactive oxygen species signaling through the Src\/Ras\/Erk1\/2 pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.121.021814","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T06:54:34Z","timestamp":1647327274000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Migraine\u2010Associated Mutation in the Na,K\u2010ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-4409","authenticated-orcid":false,"given":"Christian","family":"Staehr","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Health Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4347-8656","authenticated-orcid":false,"given":"Palle Duun","family":"Rohde","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6526-8663","authenticated-orcid":false,"given":"Nikolaj Thure","family":"Krarup","sequence":"additional","affiliation":[{"name":"Department of Cardiology Viborg Regional Hospital Viborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5353-7379","authenticated-orcid":false,"given":"Steffen","family":"Ringgaard","sequence":"additional","affiliation":[{"name":"MR Research Centre Department of Clinical Medicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0317-2911","authenticated-orcid":false,"given":"Christoffer","family":"Laustsen","sequence":"additional","affiliation":[{"name":"MR Research Centre Department of Clinical Medicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Johnsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-3474","authenticated-orcid":false,"given":"Rikke","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Health Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7763-3637","authenticated-orcid":false,"given":"Hans Christian","family":"Beck","sequence":"additional","affiliation":[{"name":"Department for Clinical Biochemistry and Pharmacology Odense University Hospital Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-0192","authenticated-orcid":false,"given":"Jens Preben","family":"Morth","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine Technical University of Denmark Kgs. 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