Insulin resistance is linked to many of the most prevalent and devastating age-related pathologies, including type 2 diabetes, cardiovascular disease and cognitive dysfunction. Skeletal muscle accounts for up to 85% of insulin-mediated blood glucose clearance, and glucose transport (GT) is a rate-controlling step for muscle glucose metabolism. Calorie restriction (CR) and exercise separately enhance insulin-mediated muscle GT in old rats, but the cellular mechanisms are poorly understood. Nothing is known about their combined effects on muscle insulin signaling or GT. The broad, long-term goal is to fully elucidate the independent and combined mechanisms for increased insulin sensitivity as the result of CR and/or exercise in older individuals. The Overall Hypothesis is: CR and exercise by old rats independently lead to increased insulin-stimulated glucose transport in skeletal muscle via distinct and overlapping mechanisms with further increases attained by the combination of CR and exercise.
The Specific Aims are: 1) Determine in old rats the effects of CR and exercise, alone and in combination, on insulin-stimulated glucose transport and GLUT4 translocation in skeletal muscle;2) Identify in old rats the specific insulin signaling events in skeletal muscle that are altered as the result of CR and exercise, alone and in combination;3) Resolve in old rats which of the signaling events that are identified as altered by CR and/or exercise are responsible for greater insulin-stimulated GT with CR and exercise, alone and in combination;4) Determine in old rats if differing shifts in lipids or glycogen in response to CR o exercise can act as triggers for the greater insulin-stimulated GT with CR and exercise, alone and in combination. Metabolic properties differ by muscle fiber type. Accordingly, muscle tissue (soleus and epitrochlearis, composed of primarily type I and type II fibers, respectively) and individually fiber-typed single fibers (GT of each fiber will be assayed by an innovative method) isolated from old rats after CR and/or exercise will be studied to discover processes that control muscle GT at both tissue and cell levels. Innovative genetic and pharmaceutical approaches will be used to elucidate mechanisms underlying CR and/or exercise benefits on GT in old rats. Greater levels of phosphorylated Akt2 (pAkt2) have been implicated as potentially pivotal for the CR-induced increase in GT. Recent data revealed the need to test if pAkt2 also contributes to greater insulin-mediated GT after exercise by older individuals. Muscle tissue and fibers from old rats after CR and/or exercise will be studied to determine: 1) novel mechanisms for enhanced pAkt2;2) if greater pAkt2 is required for greater GT;3) roles of established and newly identified Akt2 substrates in linking greater pAkt2 to increased GT;4) possible Akt2-independent mechanisms for increases in GT;5) the role of greater GLUT4 translocation in the elevated GT;and 6) unique roles of CR- and exercise-specific changes in lipids and glycogen as triggers for the CR and exercise effects on GT. The proposed research will provide novel insights into mechanisms for improved insulin sensitivity, a major health benefit of CR and/or exercise by older people.

Public Health Relevance

The proposed research is relevant to public health because insulin resistance for glucose disposal by skeletal muscle is linked to many of the most prevalent and devastating age-related disorders in older people. This project will provide valuable new knowledge regarding the independent and combined benefits of two key life- style interventions (calorie restriction and exercise) on insulin sensitivity for muscle glucose uptake. This knowledge has the potential to inform and inspire the development and optimization of strategies for improving the health of older people.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG010026-20A1
Application #
8503873
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Finkelstein, David B
Project Start
1992-05-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
20
Fiscal Year
2013
Total Cost
$370,504
Indirect Cost
$132,238
Name
University of Michigan Ann Arbor
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cartee, Gregory D (2014) Let's get real about the regulation of TBC1D1 and TBC1D4 phosphorylation in skeletal muscle. J Physiol 592:253-4
Sequea, Donel A; Sharma, Naveen; Arias, Edward B et al. (2013) Greater filamin C, GSK3*, and GSK3* serine phosphorylation in insulin-stimulated isolated skeletal muscles of calorie restricted 24 month-old rats. Mech Ageing Dev 134:60-3
Cartee, Gregory D (2010) Of mice and men: filling gaps in the TBC1D1 story. J Physiol 588:4331-2
Cartee, Gregory D; Funai, Katsuhiko (2009) Exercise and insulin: Convergence or divergence at AS160 and TBC1D1? Exerc Sport Sci Rev 37:188-95
Kim, Junghoon; Solis, Raquel S; Arias, Edward B et al. (2004) Postcontraction insulin sensitivity: relationship with contraction protocol, glycogen concentration, and 5' AMP-activated protein kinase phosphorylation. J Appl Physiol 96:575-83
McCurdy, Carrie E; Davidson, Robert T; Cartee, Gregory D (2003) Brief calorie restriction increases Akt2 phosphorylation in insulin-stimulated rat skeletal muscle. Am J Physiol Endocrinol Metab 285:E693-700
Davidson, Robert T; Arias, Edward B; Cartee, Gregory D (2002) Calorie restriction increases muscle insulin action but not IRS-1-, IRS-2-, or phosphotyrosine-PI 3-kinase. Am J Physiol Endocrinol Metab 282:E270-6
Gazdag, A C; Wetter, T J; Davidson, R T et al. (2000) Lower calorie intake enhances muscle insulin action and reduces hexosamine levels. Am J Physiol Regul Integr Comp Physiol 278:R504-12