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However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little reported. A limitation of prior investigations is their use of broad gain\/loss of mTORC1 function, mostly applied before ischemic stress. This can be circumvented by regulating one serine (S1365) on TSC2 (tuberous sclerosis complex) to achieve bidirectional mTORC1 modulation but only with TCS2-regulated costimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and is required for IPC by amplifying mTORC1 activity to favor glycolytic metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      Mice with either S1365A (TSC2\n                      <jats:sup>SA<\/jats:sup>\n                      ; phospho-null) or S1365E (TSC2\n                      <jats:sup>SE<\/jats:sup>\n                      ; phosphomimetic) knockin mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2\n                      <jats:sup>SA<\/jats:sup>\n                      mice had amplified mTORC1 activation and improved heart function compared with wild-type and TSC2\n                      <jats:sup>SE<\/jats:sup>\n                      hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2\n                      <jats:sup>SE<\/jats:sup>\n                      hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2\n                      <jats:sup>SA<\/jats:sup>\n                      , with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed\/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acylcarnitine levels declined during ischemia. The relative IR protection in TSC2\n                      <jats:sup>SA<\/jats:sup>\n                      was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in wild type and TSC2\n                      <jats:sup>SE<\/jats:sup>\n                      but not TSC2\n                      <jats:sup>SA<\/jats:sup>\n                      which had the worst post-IR function under these conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphic Abstract:<\/jats:title>\n                    <jats:p>\n                      A\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"graphic abstract\">graphic abstract<\/jats:ext-link>\n                      is available for this article.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.317710","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T05:00:28Z","timestamp":1609909228000},"page":"639-651","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury"],"prefix":"10.1161","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0816-4443","authenticated-orcid":true,"given":"Christian U.","family":"Oeing","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Cardiology, Charit\u00e9 University Medicine, Campus Virchow-Klinikum, Berlin, Germany, and German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany (C.U.O.)."},{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungho","family":"Jun","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumita","family":"Mishra","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany L.","family":"Dunkerly-Eyring","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD (B.L.D.-E., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I.","family":"Grajeda","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usman A.","family":"Tahir","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (U.A.T., R.E.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6767-7687","authenticated-orcid":true,"given":"Robert E.","family":"Gerszten","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (U.A.T., 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