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Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification\/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent\/human cardiomyocytes. 3-\u03b2-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary\/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.<\/jats:p>","DOI":"10.3390\/ijms232112909","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T05:11:33Z","timestamp":1666761093000},"page":"12909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly\u2014Rescue by Specific Amino Acid Supplementation"],"prefix":"10.3390","volume":"23","author":[{"given":"Shujin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Institute of Life Sciences, Chongqing Medical University, Chongqing 400032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-684X","authenticated-orcid":false,"given":"Dietbert","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Pathology, Maastricht University Medical Center<sup>+<\/sup>, 6200 MD Maastricht, The Netherlands"},{"name":"CARIM School for Cardiovascular Diseases, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1362-7019","authenticated-orcid":false,"given":"B. Daan","family":"Westenbrink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Schianchi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yen","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Departments of Clinical Genetics, Maastricht University Medical Center<sup>+<\/sup>, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aomin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Strzelecka","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6533-9548","authenticated-orcid":false,"given":"Jan F. C.","family":"Glatz","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Departments of Clinical Genetics, Maastricht University Medical Center<sup>+<\/sup>, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost J. F. P.","family":"Luiken","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Departments of Clinical Genetics, Maastricht University Medical Center<sup>+<\/sup>, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-1634","authenticated-orcid":false,"given":"Miranda","family":"Nabben","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"CARIM School for Cardiovascular Diseases, 6229 ER Maastricht, The Netherlands"},{"name":"Departments of Clinical Genetics, Maastricht University Medical Center<sup>+<\/sup>, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","first-page":"1555","article-title":"Lipotoxicity in obesity and diabetes-related cardiac dysfunction","volume":"1861","author":"Zlobine","year":"2016","journal-title":"Biochim. 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Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1161\/CIRCULATIONAHA.115.017355","article-title":"The Failing Heart Relies on Ketone Bodies as a Fuel","volume":"133","author":"Aubert","year":"2016","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s42255-019-0160-6","article-title":"Ketogenesis activates metabolically protective \u03b3\u03b4 T cells in visceral adipose tissue","volume":"2","author":"Goldberg","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics","volume":"25","author":"Puchalska","year":"2017","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cmet.2016.07.010","article-title":"Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes","volume":"24","author":"Cox","year":"2016","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1113\/jphysiol.1980.sp013190","article-title":"Post-exercise ketosis","volume":"301","author":"Koeslag","year":"1980","journal-title":"J. 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Echocardiogr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1002\/ehf2.13634","article-title":"Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart","volume":"8","author":"Takahara","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1530\/EJE-19-0710","article-title":"Effects of \u03b2-hydroxybutyrate on cognition in patients with type 2 diabetes","volume":"182","author":"Jensen","year":"2020","journal-title":"Eur. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.2337\/dc16-0542","article-title":"Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis","volume":"39","author":"Mudaliar","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.2337\/dc16-0330","article-title":"CV protection in the EMPA-REG OUTCOME trial: A \u201cthrifty substrate\u201d hypothesis","volume":"39","author":"Ferrannini","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1016\/j.jacc.2020.12.065","article-title":"Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC state-of-the-art review","volume":"77","author":"Yurista","year":"2021","journal-title":"J. Am. Coll. 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