Our laboratory has described in healthy humans the acute regulatory effects of both hormones and amino acids on skeletal muscle protein synthesis (growth hormone, IGF-I, amino acid mixtures (AA)) and degradation (insulin, branched-chain amino acids(BCAA)), each thereby having a net protein anabolic action. We propose to define how muscle protein metabolism is altered in three clinically important states that promote muscle protein catabolism namely, insulin-withdrawn type I diabetes, glucocorticoid excess, and burn injury. The mechanisms leading to muscle protein loss have not been well defined in these states. Using a tracer kinetic method developed for this purpose, we will define whether altered rates of proteolysis, of synthesis or of both processes are responsible. In addition, in insulin withdrawn IDDM, we will test a series of hypotheses relating to the insulin's direct antiproteolytic action as well as its indirect or permissive effects on the expression of the anabolic actions of BCAA, IGF-I and balanced AA infusions. Likewise, we will determine whether antagonism of insulin's antiproteolytic action causes muscle wasting that contributes to morbidity of glucocorticoid excess and whether glucocorticoids effect the action of other anabolic agents on muscle. Finally, the effect of insulin and IGF-I on forearm muscle in Post-burn patients will also be defined and the changes in muscle protein metabolism induced by IDDM or glucocorticoid excess compared with those following burn. In all studies, we will use steady-state tracer infusions and bilateral forearm catherization methods that have allowed us to clarify the actions of anabolic hormones and substrates in healthy humans. As recent evidence implicates the ATP-ubiquitin-proteosome system as a major proteolytic pathway in muscle, we will test whether changes in the expression of key components of this system are involved in the accelerated net protein catabolism in each of the three patient groups. Information gained from these mechanistic studies of human muscle protein metabolism should be directly relevant to the rational use of anabolic agents in the treatment or prevention of muscle wasting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038578-11
Application #
2770372
Study Section
Special Emphasis Panel (ZRG2-GMA-2 (01))
Program Officer
Laughlin, Maren R
Project Start
1987-07-01
Project End
2000-08-31
Budget Start
1998-09-15
Budget End
1999-08-31
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Keske, Michelle A; Clerk, Lucy H; Price, Wendie J et al. (2009) Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care 32:1672-7
Maier, Christina; Clodi, Martin; Neuhold, Stephanie et al. (2009) Endothelial markers may link kidney function to cardiovascular events in type 2 diabetes. Diabetes Care 32:1890-5
Clerk, Lucy H; Vincent, Michelle A; Barrett, Eugene J et al. (2007) Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiotensin-converting enzyme inhibition. Am J Physiol Endocrinol Metab 293:E1804-9
Clerk, Lucy H; Vincent, Michelle A; Jahn, Linda A et al. (2006) Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes 55:1436-42
Vincent, Michelle A; Clerk, Lucy H; Lindner, Jonathan R et al. (2006) Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab 290:E1191-7
Liu, Zhenqi; Long, Wen; Fryburg, David A et al. (2006) The regulation of body and skeletal muscle protein metabolism by hormones and amino acids. J Nutr 136:212S-7S
Wang, Hong; Liu, Zhenqi; Li, Guolian et al. (2006) The vascular endothelial cell mediates insulin transport into skeletal muscle. Am J Physiol Endocrinol Metab 291:E323-32
Vincent, Michelle A; Clerk, Lucy H; Rattigan, Stephen et al. (2005) Active role for the vasculature in the delivery of insulin to skeletal muscle. Clin Exp Pharmacol Physiol 32:302-7
Li, Guolian; Barrett, Eugene J; Wang, Hong et al. (2005) Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells. Endocrinology 146:4690-6
Vincent, Michelle A; Clerk, Lucy H; Lindner, Jonathan R et al. (2004) Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 53:1418-23

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