Des-acyl-ghrelin (DAG) normalizes hyperlactacidemia and improves survival in a lethal rat model of burn trauma |
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| Institution: | 1. Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA;2. Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA;3. Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA;3. Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington 99210-1495;4. Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019;1. Department of Medicine, University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, TN 37920, United States;2. Department of Radiology, University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, TN 37920, United States;1. Centre de recherche en Rhumatologie et Immunologie, CHU de Québec, Québec, QC, Canada G1V 4G2;2. Pfizer''s Cardiovascular and Metabolic Diseases Research Unit, Cambridge, MA 02139, USA;3. Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal, Montreal, QC, Canada H2W 1R7 |
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| 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 24 h 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 24 h of injury. |
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| Keywords: | Burn injury Des-acyl-ghrelin (DAG) Hyperlactacidemia PDC activity PDK Survival |
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