Advancing age is typically accompanied by insulin resistance. Relatively little, however, is known concerning the cellular mechanism(s) responsible for age-related insulin resistance, particularly in the primary target tissue for insulin action, skeletal muscle. In the current proposal, the hypothesis to be tested is that the insulin signal leading to glucose transport is impaired with the aging process in human skeletal muscle, which subsequently contributes to insulin resistance. Our working hypothesis is that insulin signal transduction is reduced in aged skeletal muscle due to inhibition from increased muscle lipid content and/or reduced oxidative capacity. As decrements during the aging process can be a consequence of physical inactivity, our secondary hypothesis is that age-related insulin resistance is compensated for with exercise training by enhanced insulin signaling. The following aims will test these hypotheses.
Specific Aim 1 : Determine if insulin signal transduction is impaired with aging in human skeletal muscle. We will examine if insulin signal transduction in skeletal muscle is impaired with the aging process in humans and if muscle lipid accumulation and/or impaired oxidative capacity contribute to the decrement.
Specific Aim 2 : Determine if lipid accumulation and or reduced muscle oxidative capacity impairs insulin signal transduction in human skeletal muscle. Using a primary human skeletal muscle cell culture system we will determine if lipid exposure impairs insulin signaling and if decrements in lipid oxidation (akin to aging) induce insulin resistance. With PPARa agonist treatment we will conversely increase muscle oxidative capacity in muscle cells and in aged individuals and determine if this increase reverses lipid-induced insulin resistance.
Specific Aim 3 : Determine the cellular mechanism(s) by which insulin action is enhanced with physical activity in aged skeletal muscle. We will determine if enhanced insulin signal transduction contributes to the improvement in insulin action seen with endurance- and resistance-oriented exercise training in aged individuals and if changes in muscle lipid content and/or oxidative capacity are mechanisms that can explain such changes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG025205-01A1S1
Application #
7214521
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Williams, John
Project Start
2005-09-15
Project End
2010-06-30
Budget Start
2006-04-15
Budget End
2006-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$2,565
Indirect Cost
Name
East Carolina University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Consitt, Leslie A; Koves, Timothy R; Muoio, Deborah M et al. (2016) Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction. Biochem Biophys Res Commun 479:868-874
Consitt, Leslie A; Van Meter, Jessica; Newton, Christopher A et al. (2013) Impairments in site-specific AS160 phosphorylation and effects of exercise training. Diabetes 62:3437-47
Boyle, K E; Zheng, D; Anderson, E J et al. (2012) Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans. Int J Obes (Lond) 36:1025-31
Kovalik, Jean-Paul; Slentz, Dorothy; Stevens, Robert D et al. (2011) Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system. Diabetes 60:1882-93
Boyle, K E; Canham, J P; Consitt, L A et al. (2011) A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals. J Clin Endocrinol Metab 96:775-81
Consitt, Leslie A; Bell, Jill A; Koves, Timothy R et al. (2010) Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals. Diabetes 59:1407-15
Consitt, Leslie A; Bell, Jill A; Houmard, Joseph A (2009) Intramuscular lipid metabolism, insulin action, and obesity. IUBMB Life 61:47-55
Consitt, Leslie A; Wideman, Laurie; Hickey, Matthew S et al. (2008) Phosphorylation of the JAK2-STAT5 pathway in response to acute aerobic exercise. Med Sci Sports Exerc 40:1031-8