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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Finkelstein, David B
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University of Michigan Ann Arbor
Other Domestic Higher Education
Ann Arbor
United States
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Wang, Haiyan; Sharma, Naveen; Arias, Edward B et al. (2016) Insulin Signaling and Glucose Uptake in the Soleus Muscle of 30-Month-Old Rats After Calorie Restriction With or Without Acute Exercise. J Gerontol A Biol Sci Med Sci 71:323-32
Sharma, Naveen; Arias, Edward B; Cartee, Gregory D (2016) Inhibition of Akt2 phosphorylation abolishes the calorie restriction-induced improvement in insulin-stimulated glucose uptake by rat soleus muscle. Appl Physiol Nutr Metab 41:1208-1211
Wang, Haiyan; Arias, Edward B; Cartee, Gregory D (2016) Calorie restriction leads to greater Akt2 activity and glucose uptake by insulin-stimulated skeletal muscle from old rats. Am J Physiol Regul Integr Comp Physiol 310:R449-58
Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M et al. (2016) Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab 23:1034-47
Cartee, Gregory D (2015) Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 58:19-30
Sharma, Naveen; Wang, Haiyan; Arias, Edward B et al. (2015) Mechanisms for independent and combined effects of calorie restriction and acute exercise on insulin-stimulated glucose uptake by skeletal muscle of old rats. Am J Physiol Endocrinol Metab 308:E603-12
Sharma, Naveen; Sequea, Donel A; Castorena, Carlos M et al. (2014) Heterogeneous effects of calorie restriction on in vivo glucose uptake and insulin signaling of individual rat skeletal muscles. PLoS One 8:e65118
Cartee, Gregory D (2014) Let's get real about the regulation of TBC1D1 and TBC1D4 phosphorylation in skeletal muscle. J Physiol 592:253-4
Xiao, Yuanyuan; Sharma, Naveen; Arias, Edward B et al. (2013) A persistent increase in insulin-stimulated glucose uptake by both fast-twitch and slow-twitch skeletal muscles after a single exercise session by old rats. Age (Dordr) 35:573-82
Sharma, Naveen; Castorena, Carlos M; Cartee, Gregory D (2012) Tissue-specific responses of IGF-1/insulin and mTOR signaling in calorie restricted rats. PLoS One 7:e38835

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