Our general hypothesis is that a reduced response of muscle protein anabolism to insulin plays an important role in the loss of muscle mass that takes place with aging. We further hypothesize that this alteration is specific for protein metabolism regardless of glucose tolerance status. Our preliminary results suggest that there is an alteration in the response of muscle anabolism to insulin in the elderly, which can compromise the positive effect of amino acids on postprandial muscle protein gain. The goal of this proposal is to define the age-related changes in insulin stimulated muscle protein anabolism, in order to be able to develop specific interventions to reduce or reverse the loss of muscle mass with aging. We will test the hypothesis that the responsiveness of muscle myofibrillar and mixed protein synthesis and breakdown to insulin is reduced in healthy elderly volunteers and in young healthy controls. Insulin will be infused locally in the femoral artery in order to expose the muscle tissue to specific insulin concentrations and avoids as much as possible the systemic effects of hyperinsulinemia (i.e. hypoaminoacidemia and hypoglycemia). Since the defect of muscle protein anabolism in the elderly might be either generalized for any insulin concentration, or dose-dependent, i.e. specifically localized to a certain insulin level (e.g. prandial), we will measure muscle protein kinetics at graded insulin infusion rates that will increase insulin concentration in the femoral vein to approximatley 30 muU/ml (low dose), approximately 80 muU/ml (prandial dose), approximately 200 muU/ml (high dose). To address the issue as to whether the age-related alteration in the response of muscle protein metabolism to insulin is independent or glucose tolerance, we will measure muscle and whole body glucose kinetics simultaneously with protein kinetics not only in the healthy young and elderly volunteers, but also in young and elderly type 2 diabetes patients. The inclusion of these two additional groups of type 2 diabetic patients will allow us to test if the effects of insulin resistance (type 2 diabetes) and age on muscle protein and glucose metabolism are indpendent.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG018311-07
Application #
6988929
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Dutta, Chhanda
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2005-01-01
Budget End
2005-08-31
Support Year
7
Fiscal Year
2004
Total Cost
$325,000
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Markofski, Melissa M; Dickinson, Jared M; Drummond, Micah J et al. (2015) Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. Exp Gerontol 65:1-7
Dickinson, Jared M; Volpi, Elena; Rasmussen, Blake B (2013) Exercise and nutrition to target protein synthesis impairments in aging skeletal muscle. Exerc Sport Sci Rev 41:216-23
Timmerman, K L; Volpi, E (2013) Endothelial function and the regulation of muscle protein anabolism in older adults. Nutr Metab Cardiovasc Dis 23 Suppl 1:S44-50
Drummond, Micah J; Timmerman, Kyle L; Markofski, Melissa M et al. (2013) Short-term bed rest increases TLR4 and IL-6 expression in skeletal muscle of older adults. Am J Physiol Regul Integr Comp Physiol 305:R216-23
Dickinson, Jared M; Drummond, Micah J; Coben, Jennifer R et al. (2013) Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise. Clin Nutr 32:273-80
Timmerman, Kyle L; Dhanani, Shaheen; Glynn, Erin L et al. (2012) A moderate acute increase in physical activity enhances nutritive flow and the muscle protein anabolic response to mixed nutrient intake in older adults. Am J Clin Nutr 95:1403-12
Drummond, Micah J; Dickinson, Jared M; Fry, Christopher S et al. (2012) Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults. Am J Physiol Endocrinol Metab 302:E1113-22
Drummond, Micah J; McCarthy, John J; Sinha, Mala et al. (2011) Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol Genomics 43:595-603
Timmerman, Kyle L; Lee, Jessica L; Dreyer, Hans C et al. (2010) Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling. J Clin Endocrinol Metab 95:3848-57
Timmerman, Kyle L; Lee, Jessica L; Fujita, Satoshi et al. (2010) Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults. Diabetes 59:2764-71

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