Renán Orellana, M.D., FAAP
Assistant Professor of Pediatrics
Section of Critical Care
Department of Pediatrics
Baylor College of Medicine
Control Mechanisms of Protein Metabolism in Skeletal Muscle During Sepsis
The purpose of Dr. Orellana's research efforts is to determine the effect of sepsis on muscle proteolysis during development and whether this effect can be modified by specific amino acid therapies designed to support patients during the sepsis-induced systemic inflammatory response and organ dysfunction, with the purpose of enhancing recovery and survival during critical illness.
Sepsis is associated with hypermetabolism, activation of peripheral protein catabolism, and alterations in the flux of metabolic substrates between skeletal muscle and liver, in an attempt to maintain the balance between peripheral substrate stores and the increased metabolic demands required to activate the immune system and the stress response. In skeletal muscle of adults, sepsis reduces protein synthesis by depressing translation initiation and induces resistance to insulin and branched-chain amino acid stimulation. In contrast, healthy neonates and growing mammals maintain a high basal muscle protein synthesis rate that is very sensitive to insulin and amino acid stimulation. We have examined the effects of sepsis on the insulin-amino acid interface in skeletal muscle during development by applying novel hormone-substrate clamp techniques, and the translational mechanisms that control protein deposition in skeletal muscle during sepsis. Future research will investigate if energetic dysregulation modulates the alterations in translation initiation signaling in muscle of septic neonatal pigs and if specific amino acid therapies in conjunction with pharmacologic treatment of the sepsis-induced metabolic dysregulation supports the inflammatory response and minimizes the catabolic effects of sepsis in skeletal muscle.
Understanding the mechanisms that regulate protein synthesis in neonatal animals during acute inflammation and its ability to protect against catabolism during sepsis may help design effective nutritional strategies to alleviate the catabolic response triggered by sepsis.
Suryawan A, Orellana RA, Nguyen HV, Jeyapalan AS, Fleming JR, Davis TA. Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1597-605. Epub 2007 Sep 18.PMID: 17878222 [PubMed - indexed for MEDLINE]
Orellana RA, Jeyapalan A, Escobar J, Frank JW, Nguyen HV, Suryawan A, Davis TA. Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation. Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1416-25. Epub 2007 Sep 11.PMID: 17848637 [PubMed - indexed for MEDLINE]
Davis TA, Suryawan A, Orellana RA, Nguyen HV, Fiorotto ML. Postnatal ontogeny of skeletal muscle protein synthesis in pigs.J Anim Sci. 2008 Apr;86(14 Suppl):E13-8. Epub 2007 Sep 4.PMID: 17785597 [PubMed - in process]
Jeyapalan AS, Orellana RA, Suryawan A, O'Connor PM, Nguyen HV, Escobar J, Frank JW, Davis TA. Glucose stimulates protein synthesis in skeletal muscle of neonatal pigs through an AMPK- and mTOR-independent process.Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E595-603
Orellana RA, Kimball SR, Suryawan A, Escobar J, Nguyen HV, Jefferson LS, Davis TA. Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation. Am J Physiol Endocrinol Metab. 2007, Feb; 292(2):E629-36. Epub 2006 Oct 17.
Orellana RA, O'Connor PMJ, Nguyen HV, Bush JA, Thivierge MC, Suryawan A, Fiorotto ML, Davis TA. Modulation of Muscle Protein Synthesis by Insulin is Maintained During Acute Neonatal Endotoxemia. Am J Physiol Endocrinol Metab. 2006, Jul; 291(1):E159-66. Epub 2006 Feb 14.
Thivierge MC, Bush JA, Suryawan A, Nguyen HV, Orellana RA, Burrin DG, Jahoor F, Davis TA. Whole-Body and Hindlimb Protein Breakdown Are Differentially Altered by Feeding in Neonatal Piglets. J Nutr. 2005 Jun;135(6):1430-1437.
Orellana RA, Kimball SR, Nguyen HV, Bush JA, Suryawan A, Thivierge MC, Jefferson LS, Davis TA .Regulation of muscle protein synthesis in neonatal pigs during prolonged endotoxemia. Pediatr Res 2004 Mar;55(3):442-9. Epub 2003 Dec 17.
Bush JA, Kimball SR, O’Connor PMJ, Suryawan AS, Orellana RA, Nguyen HV, Jefferson LS, and Davis TA. Translational control of protein synthesis in muscle and liver of growth-hormone-treated pigs. Endocrinology 144:1273-1283, 2003.
Kimball SR, Orellana RA, O'Connor PMJ, Bush JA, Thivierge MC, Suryawan A, Nguyen HV, Jefferson LS, Davis TA. Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs. Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E637-44. Epub 2003 May 28.).
Orellana RA, O'Connor PMJ, Nguyen HV, Bush JA, Thivierge MC, Suryawan A, Fiorotto ML, Davis TA : Endotoxemia reduces muscle protein synthesis in neonates. Am J Physiol Endocrinol Metab 283: E909-916, 2002.