Increased post-exercise (PEX) insulin sensitivity, first demonstrated in 1982, is among the best documented exercise benefits linked to improved health, but identification of the mechanism has been elusive. Exercise by lean, normal individuals has little effect on proximal insulin signaling, suggesting exercise alters a distal site. Progress stalled until the discovery of a sustained PEX increase in the most distal signaling step known to be crucial for glucose transport (GT): phosphorylation of Akt Substrate of 160 kDa (AS160). The sustained PEX increase in phosphorylated AS160 (pAS160) tracks closely with elevated insulin-induced GT in lean rats, and sustained pAS160 is also found in muscle of lean humans PEX. Increased pAS160 has emerged as an attractive candidate to explain improved insulin sensitivity PEX. The broad, long-term goal is to fully elucidate the mechanisms that underlie enhanced insulin sensitivity PEX. The 3 Specific Aims are: 1) Identify the mechanism for the sustained increase in AS160 phosphorylation in skeletal muscle of lean rats after exercise. 2) By expressing in rat skeletal muscle AS160 that is genetically modified to prevent phosphorylation on key sites, determine AS160's role in exercise-induced changes in GT in lean rats. 3) Identify the similarities and differences between lean and obese rats in the specific mechanisms for their respective exercise-induced improvements in insulin-stimulated GT. Evidence indicates the sustained PEX increase in pAS160 is not attributable to persistent activation of kinases. A novel idea to be tested is that the sustained elevation in pAS160 is because of attenuated AS160 dephosphorylation by Ser/Thr protein phosphatases. Because preliminary data implicate protein phosphatase 2A (PP2A) in AS160 dephosphorylation, multiple approaches will be used for Aim 1 to probe PP2A's regulation of pAS160.
Aim 2 will use an innovative method to measure GT by single muscle fibers that are matched for fiber type, but differ by expression of wildtype AS160 or AS160 genetically modified to prevent phosphorylation on key sites to learn if the improved PEX insulin-mediated GT in lean rats is attributable to greater pAS160.
Aim 3 will determine if the well-known exercise benefits on insulin sensitivity for lean and obese rats are accrued by distinct mechanisms. Exercise by obese rats is predicted to reduce high muscle levels of mediators of insulin resistance (inducible nitric oxide synthase;protein S- nitrosylation;lipid metabolites;JNK, IKK &PKC? activation) leading to enhanced insulin signaling and GT. However, in muscles from lean rats, exercise is predicted to not greatly alter their already low levels of mediators or normal levels of proximal insulin signaling. The sustained increase in pAS160 PEX observed in lean humans was reported to be less in obese people. Accordingly, experiments will be performed to test if the greater PEX insulin-mediated GT previously found for lean vs. obese rats is attributable to greater pAS160 PEX in lean rats. Completion of the proposed research will provide novel insights into the specific mechanisms that account for improved insulin sensitivity, a major health benefit for both lean and obese individuals.
The proposed research is relevant to public health because insulin resistance for glucose disposal by skeletal muscle is an essential and perhaps primary defect for Type 2 diabetes, and exercise can greatly improve insulin-mediated glucose uptake. Because of the related epidemics of obesity, insulin resistance and diabetes, it is crucial to elucidate mechanisms for improved insulin sensitivity in insulin resistant individuals. It is also important to understand mechanisms for improved insulin sensitivity in normal individuals because the level of insulin sensitivity found in sedentary lean individuals may not confer optimal health and because identifying mechanisms in healthy individuals has the potential to inspire the development of new therapies that benefit insulin-resistant people.
|Ludzki, Alison C; Pataky, Mark W; Cartee, Gregory D et al. (2018) Acute endurance exercise increases Vegfa mRNA expression in adipose tissue of rats during the early stages of weight gain. Appl Physiol Nutr Metab 43:751-754|
|Oki, Kentaro; Arias, Edward B; Kanzaki, Makoto et al. (2018) Prior treatment with the AMPK activator AICAR induces subsequently enhanced glucose uptake in isolated skeletal muscles from 24-month-old rats. Appl Physiol Nutr Metab 43:795-805|
|Arias, E B; Wang, H; Cartee, G D (2018) Akt substrate of 160 kDa dephosphorylation rate is reduced in insulin-stimulated rat skeletal muscle after acute exercise. Physiol Res 67:143-147|
|Pataky, Mark W; Wang, Haiyan; Yu, Carmen S et al. (2017) High-Fat Diet-Induced Insulin Resistance in Single Skeletal Muscle Fibers is Fiber Type Selective. Sci Rep 7:13642|
|Zheng, Xiaohua; Cartee, Gregory D (2016) Insulin-induced Effects on the Subcellular Localization of AKT1, AKT2 and AS160 in Rat Skeletal Muscle. Sci Rep 6:39230|
|Sharma, Pragya; Arias, Edward B; Cartee, Gregory D (2016) Protein Phosphatase 1-? Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle. Diabetes 65:2606-17|
|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|
|Cartee, Gregory D; Arias, Edward B; Yu, Carmen S et al. (2016) Novel single skeletal muscle fiber analysis reveals a fiber type-selective effect of acute exercise on glucose uptake. Am J Physiol Endocrinol Metab 311:E818-E824|
|Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M et al. (2016) Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab 23:1034-1047|
|Castorena, Carlos M; Arias, Edward B; Sharma, Naveen et al. (2015) Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-?B pathways in rat skeletal muscle. Appl Physiol Nutr Metab 40:251-62|
Showing the most recent 10 out of 32 publications