The broad, long-range objectives of this project are to identify the mechanisms for age-related skeletal muscle insulin-resistance, to determine if the defect is primarily insulin-resistance or a reduction in the ability to elevate glucose transport by various stimuli (including exercise), to determine if the age-related defect is inevitable or if old muscle retains the capacity to upregulate glucose transport, and to determine if age modifies the increased insulin sensitivity after exercise. Insulin- and exercise-stimulation will be studied because of their physiological importance in the regulation of muscle glucose metabolism. Fischer 344 rats (12, 18 or 24 mos of age) will be the animal model because they remain lean throughout their lifespan, enabling the effects of age to be studied independent of obesity, which has confounded interpretation of earlier studies.
The Specific Aims are to determine the effect of age on 1) the insulin-stimulated increase of glucose transport rate and sarcolemmal glucose transporter content, 2) the capacity of moderate caloric restriction to cause upregulation of glucose transport, 3) the contraction- stimulated increase of glucose transport rate and sarcolemmal glucose transporter content, and 4) the enhanced insulin-stimulated glucose transport rate following contractile activity. The health-relatedness of the project is that advancing age is characterized by an increased prevalence of hyperglycemia and hyperinsulinemia. These conditions are associated with a greater risk for many age-related diseases, including hypertension, cardiovascular and cerebrovascular disease. The cellular mechanisms responsible for the insulin resistance in older individuals are undetermined, but skeletal muscle, quantitatively the major insulin- sensitive tissue, plays a pivotal role. Muscle glucose transport will be studied because it is the rate-limiting step for muscle glucose metabolism and preliminary evidence indicates a defect at this site. The model to be used to study glucose transport rate will be the perfused hindlimb muscle preparation. Electrically stimulated contractile activity will be used as a model for in vivo exercise in order to isolate, as much as possible, age- related changes in the skeletal muscle from changes in other tissues. Moderate caloric restriction, identified by preliminary research as the only intervention known to reverse the insulin-resistance of old muscle, will be used as an experimental probe to determine the mechanism by which old muscle can upregulate its glucose transport system.

National Institute of Health (NIH)
National Institute on Aging (NIA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Respiratory and Applied Physiology Study Section (RAP)
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University of Wisconsin Madison
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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
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; 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
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; 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
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
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
Mackrell, James G; Arias, Edward B; Cartee, Gregory D (2012) Fiber type-specific differences in glucose uptake by single fibers from skeletal muscles of 9- and 25-month-old rats. J Gerontol A Biol Sci Med Sci 67:1286-94
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
Sharma, Naveen; Sequea, Donel A; Arias, Edward B et al. (2012) Greater insulin-mediated Akt phosphorylation concomitant with heterogeneous effects on phosphorylation of Akt substrates in soleus of calorie-restricted rats. Am J Physiol Regul Integr Comp Physiol 303:R1261-7

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