{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:10:21Z","timestamp":1790482221468,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2016,10,23]],"date-time":"2016-10-23T00:00:00Z","timestamp":1477180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 DK 83414"],"award-info":[{"award-number":["RO1 DK 83414"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AA 022742"],"award-info":[{"award-number":["R21 AA 022742"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 AA02433\u201001\u20108236"],"award-info":[{"award-number":["P50 AA02433\u201001\u20108236"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,12,15]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD\n                            <jats:sup>+<\/jats:sup>\n                            \/NADH ratio and ATP content.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell\u2010permeable ester of \u03b1KG reversed the lower TCA cycle intermediate concentrations and increased ATP content.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non\u2010hepatic ammonia disposal. Non\u2010hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from \u03b1\u2010ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I\/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell\u2010permeable ester of \u03b1\u2010ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia\u2010induced mitochondrial dysfunction is a novel therapeutic approach.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp272796","type":"journal-article","created":{"date-parts":[[2016,8,25]],"date-time":"2016-08-25T05:24:49Z","timestamp":1472102689000},"page":"7341-7360","source":"Crossref","is-referenced-by-count":163,"title":["Hyperammonaemia\u2010induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress"],"prefix":"10.1113","volume":"594","author":[{"given":"Gangarao","family":"Davuluri","sequence":"first","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allawy","family":"Allawy","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samjhana","family":"Thapaliya","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie H.","family":"Rennison","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmvir","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yana","family":"Sandlers","sequence":"additional","affiliation":[{"name":"Department of Chemistry Cleveland State University  SR 364, 2351 Euclid Avenue Cleveland OH 44115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Van Wagoner","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris A.","family":"Flask","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering School of Medicine Case Western Reserve University  10900 Euclid Avenue Cleveland OH 44106 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Hoppel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Medicine School of Medicine Case Western Reserve University  10900 Euclid Avenue Cleveland OH 44106 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takhar","family":"Kasumov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeast Ohio Medical University  4209 State Route 44 Rootstown OH 44272"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1774-0104","authenticated-orcid":false,"given":"Srinivasan","family":"Dasarathy","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"},{"name":"Department of Gastroenterology Cleveland Clinic  9500 Euclid Avenue Cleveland OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,10,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.10.001"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.2808"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-198012000-00008"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(55)90178-2"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(77)90035-2"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00164106"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(89)90518-0"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.11.048"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304854200"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13264"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00202.2004"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.08.032"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/lt.24506"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000911"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glp066"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2008.04.031"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(76)90075-5"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.04.002"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00235522"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-1989-8_13"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aquatox.2010.04.007"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/40.3.281"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.1982.tb02222.x"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-013-9428-9"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3801"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3480981"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.25451"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(90)90131-2"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-009-6208-1"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715769709097867"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1986.tb00768.x"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.03.040"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109322"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(99)00042-6"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.1984.12005719"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.1222"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(79)90738-3"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-008-9122-5"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R200006200"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1317049110"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00183.2012"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022406911604"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2005.04.004"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1996.271.4.C1380"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1997.77.3.731"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107410"},{"key":"e_1_2_6_48_1","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1093\/ajcn\/26.9.916","article-title":"Comparison of the effect of various amino acids upon the blood ammonia concentration of patients with liver disease","volume":"26","author":"Rudman D","year":"1973","journal-title":"Am J Clin Nutr"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1990.259.5.C834"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.07.007"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-007-9422-x"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:29:3:279"},{"key":"e_1_2_6_54_1","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1096\/fasebj.5.8.1827082","article-title":"Regulation of muscle carbohydrate metabolism during exercise","volume":"5","author":"Stanley WC","year":"1991","journal-title":"FASEB J"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2728(88)90014-X"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00105.2009"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1027374931887"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1910421"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1249\/00003677-199800260-00013"},{"key":"e_1_2_6_60_1","doi-asserted-by":"crossref","first-page":"L150","DOI":"10.1152\/ajplung.1996.271.1.L150","article-title":"Redox regulation of manganese superoxide dismutase","volume":"271","author":"Warner BB","year":"1996","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2013.02.010"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22917"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-013-9382-6"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0343961"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP272796","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP272796","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP272796","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T06:50:32Z","timestamp":1696143032000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP272796"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,23]]},"references-count":63,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2016,12,15]]}},"alternative-id":["10.1113\/JP272796"],"URL":"https:\/\/doi.org\/10.1113\/jp272796","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,23]]}}}