title: Des-acyl-ghrelin (DAG) normalizes hyperlactacidemia and improves survival in a lethal rat model of burn trauma.
abstract: Critical illness, including burn injury, results in elevated plasma lactate levels. Dysregulation of PI3K/Akt signaling has been shown to play a predominant role in the inactivation of skeletal muscle PDC and, hence, in hyperlactacidemia in rat models of sepsis and endotoxemia. This observation, and our previous finding that DAG can reverse burn-induced skeletal muscle proteolysis through the activation of PI3K/Akt pathway, led us to hypothesize that DAG may also attenuate hyperlactacidemia in burn injury. Our investigations revealed that burn injury significantly elevated both skeletal muscle lactate production and plasma lactate levels. Moreover, this was accompanied in skeletal muscle by a 5-7 fold increase in mRNA expression of pyruvate dehydrogenase kinases (PDK) 2 and 4, and a ∼30% reduction in PDC activity. DAG treatment of burn rats completely normalized not only the mRNA expression of the PDKs and PDC activity, but also hyperlactacidemia within 24h of burn injury. DAG also normalized epinephrine-induced lactate production by isolated skeletal muscles from normal rats. Moreover, DAG also improved survival in a lethal rat model of burn trauma. These findings with DAG may have clinical implications because chances of survival for critically ill patients are greatly improved if plasma lactate levels are normalized within 24h of injury.
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Sulaiman
authors: S
authors: Sheriff
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Nijiati
authors: N
authors: Kadeer
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Lou Ann
authors: LA
authors: Friend
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: J Howard
authors: JH
authors: James
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: J Wesley
authors: JW
authors: Alexander
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA. Electronic address: ambi.bala@uc.edu.
authors: Ambikaipakan
authors: A
authors: Balasubramaniam
mesh_terms: D000818:Animals; D002056:Burns / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D054439:Ghrelin / Q000008:administration & dosage / Q000627:therapeutic use*; D019344:Lactic Acid / Q000097:blood* / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D059748:Proteolysis; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
chemical_list: D054439:Ghrelin; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; C422650:ghrelin, des-n-octanoyl; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases
keywords: Burn injury; Des-acyl-ghrelin (DAG); Hyperlactacidemia; PDC activity; PDK; Survival