1 40 1 Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. URL Address <a href="http://doi.org/10.1113/JP272796" target="_blank" rel="noreferrer noopener">http://doi.org/10.1113/JP272796</a> Pages 7341–7360 Issue 24 Volume 594 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. Publisher An entity responsible for making the resource available The Journal of physiology Date A point or period of time associated with an event in the lifecycle of the resource 2016 2016-12 Subject The topic of the resource *ammonia; *ATP; *cellular respiration; *cirrhosis; *mitochondria; *Oxidative Stress; *portacaval anastamosis; *reactive oxygen species; *skeletal muscle; Adenosine Triphosphate/metabolism; Aged; Animals; Cell Line; Cell Respiration; Creatine Kinase/metabolism; Female; Humans; Hyperammonemia/*metabolism; Liver Cirrhosis/metabolism; Male; Middle Aged; Mitochondria; Muscle; Muscle/*metabolism; Myosin Heavy Chains/metabolism; NAD/metabolism; Rats; Reactive Oxygen Species/metabolism; Skeletal/*metabolism; Sprague-Dawley; Thiobarbituric Acid Reactive Substances/metabolism Creator An entity primarily responsible for making the resource Davuluri Gangarao; Allawy Allawy; Thapaliya Samjhana; Rennison Julie H; Singh Dharmvir; Kumar Avinash; Sandlers Yana; Van Wagoner David R; Flask Chris A; Hoppel Charles; Kasumov Takhar; Dasarathy Srinivasan Description An account of the resource KEY POINTS: Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD(+) /NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids. Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell-permeable ester of alphaKG reversed the lower TCA cycle intermediate concentrations and increased ATP content. 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. ABSTRACT: 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-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from alpha-ketoglutarate 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(+) /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-permeable ester of alpha-ketoglutarate 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-induced mitochondrial dysfunction is a novel therapeutic approach. Identifier An unambiguous reference to the resource within a given context <a href="http://doi.org/10.1113/JP272796" target="_blank" rel="noreferrer noopener">10.1113/JP272796</a> Rights Information about rights held in and over the resource Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s). *ammonia *ATP *cellular respiration *cirrhosis *Mitochondria *Oxidative Stress *portacaval anastamosis *Reactive oxygen species *skeletal muscle 2016 Adenosine Triphosphate/metabolism Aged Allawy Allawy Animals Cell Line Cell Respiration Creatine Kinase/metabolism Dasarathy Srinivasan Davuluri Gangarao Department of Pharmaceutical Sciences Female Flask Chris A Hoppel Charles Humans Hyperammonemia/*metabolism Kasumov Takhar Kumar Avinash Liver Cirrhosis/metabolism Male Middle Aged Mitochondria Muscle Muscle/*metabolism Myosin Heavy Chains/metabolism NAD/metabolism NEOMED College of Pharmacy Rats Reactive Oxygen Species/metabolism Rennison Julie H Sandlers Yana Singh Dharmvir Skeletal/*metabolism Sprague-Dawley Thapaliya Samjhana The Journal of physiology Thiobarbituric Acid Reactive Substances/metabolism Van Wagoner David R