{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:06:22Z","timestamp":1787022382529,"version":"build-2736575974"},"reference-count":60,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K08452"],"award-info":[{"award-number":["20K08452"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013236","name":"MSD Life Science Foundation, Public Interest Incorporated Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013236","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Systemic branched\u2010chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long\u2010Evans\u2010Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched\u2010chain \u03b1\u2010keto acid dehydrogenase (BCKDH), a rate\u2010limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long\u2010Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH\u2010E1\u03b1 subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3\u2010E1\u03b1 interaction compared to LETO rats. Knocking down E1\u03b1 expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3\u2010BCKDH expressions observed in OLETF rat hearts. E1\u03b1 knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3\u2010BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.<\/jats:p>","DOI":"10.14814\/phy2.15608","type":"journal-article","created":{"date-parts":[[2023,2,18]],"date-time":"2023-02-18T12:42:00Z","timestamp":1676724120000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Downregulation of extramitochondrial\n                    <scp>BCKDH<\/scp>\n                    and its uncoupling from\n                    <scp>AMP<\/scp>\n                    deaminase in type 2 diabetic\n                    <scp>OLETF<\/scp>\n                    rat hearts"],"prefix":"10.14814","volume":"11","author":[{"given":"Toshifumi","family":"Ogawa","sequence":"first","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7815-1464","authenticated-orcid":false,"given":"Hidemichi","family":"Kouzu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arata","family":"Osanami","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tatekoshi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-1772","authenticated-orcid":false,"given":"Tatsuya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Cellular Physiology and Signal Transduction Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kuno","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yugo","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoya","family":"Ino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Toda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Ohwada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Tanno","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Miki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5024-7085","authenticated-orcid":false,"given":"Tetsuji","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine Sapporo Medical University School of Medicine  Sapporo Japan"},{"name":"Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences Hokkaido University of Science  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101392"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmb.2005.494033032469"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.221713"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273097"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.011625"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(00)24250-X"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1270"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00097.2018"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033704"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2439"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4245"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.205385"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01036-12"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2021.01.002"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.01.004"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.05.167"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316738"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0610com"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.11.005"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0630588100"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.049817"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2009"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1499107"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.171"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02213-1"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203473200"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569\u2010022\u201000760\u20103"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0227-4"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0158"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-012-9313-3"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7670"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154864"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13741"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.113.000672"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc8861"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-020518-114455"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.10.013"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.06.003"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00244.2002"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.531384"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/201625"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00129.2012"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05362-7"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01248.2009"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.5.H2124"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.020226"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.046"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2018.05.003"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2021.115654"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154871"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-019-0892-3"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21962-2"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0132-2"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00114.2016"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25003"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2009.09.023"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.04.015"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav0558"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.151"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.351031"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15608","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.14814\/phy2.15608","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15608","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T22:25:04Z","timestamp":1704839104000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.15608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2]]},"references-count":60,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.14814\/phy2.15608"],"URL":"https:\/\/doi.org\/10.14814\/phy2.15608","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2]]},"assertion":[{"value":"2022-12-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e15608"}}