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Increased phosphorylation of the 70-kDa ribosomal S6 kinase (p70S6k) signaling is strongly correlated with the degree of muscle adaptation following exercise. Herein we compare the phosphorylation of p70S6k, Akt, and mammalian target of rapamycin (mTOR) in the tibialis anterior (TA) muscles of lean and obese Zucker rats following a bout of eccentric exercise. Exercise increased p70S6k (Thr389) phosphorylation immediately after (33.3 ± 7.2%) and during [1 h (24.0 ± 14.9%) and 3 h (24.6 ± 11.3%)] recovery in the lean TA and at 3 h (33.5 ± 8.0%) in the obese TA Zucker rats. mTOR (Ser2448) phosphorylation was elevated in the lean TA immediately after exercise (96.5 ± 40.3%) but remained unaltered in the obese TA. Exercise increased Akt (Thr308) and Akt (Ser473) phosphorylation in the lean but not the obese TA. These results suggest that insulin resistance is associated with alterations in the ability of muscle to activate p70S6k signaling following an acute bout of exercise. Muscle Nerve 39: 503–511 2009.

Type 2 (non–insulin-dependent) diabetes mellitus (DM) is an emerging epidemic in Western cultures, and it is believed to afflict 150 million people worldwide.11 Insulin resistance is frequently accompanied by a variety of metabolic and cardiovascular abnormalities, including hypertension, glucose intolerance, type 2 diabetes, dyslipidemia, atherosclerosis, and central obesity. A number of studies that employ strength training regimens have been shown to improve glycemic control, increase skeletal muscle size and strength, and positively change body composition. The data suggest that anaerobic exercise may be an effective strategy for the treatment of insulin resistance and type 2 diabetes.6, 7, 49, 53 Recent reports have suggested that differences exist between normal and insulin-resistant muscle in their adaptation to an exercise regimen.5, 8, 20, 24, 48, 50 However, the direct effects of exercise on the phenotype of insulin-resistant muscle have not been widely studied. It is thought that the beneficial effects of exercise on muscle are mediated through activation of the various signaling cascades involved in regulating changes in gene expression, glucose uptake, and protein synthesis.2Whether insulin resistance alters exercise-induced signal transduction processes in muscle is unknown, but the differences, if present, may help to explain why exercise-induced skeletal muscle adaptations can differ between normal and insulin-resistant populations.

It is well established that increased muscle loading increases the rates of muscle protein synthesis.27 This increase in protein synthesis, at least in part, is thought to be regulated by the phosphorylation of the p70 ribosomal protein S6 kinase (p70S6k),26 whose activation has been proposed to promote increased translation of messages that have a polypyrimide motif just downstream of the 5′ cap.45 It is believed that p70S6k activity is regulated by the mammalian target of rapamycin (mTOR), which functions as a growth factor and nutrient-sensing signaling molecule in mammalian cells.40 How mTOR activity is modulated is not clear; however, recent evidence suggests that mTOR is controlled by Akt or protein kinase B (PKB), which is activated in response to phospholipid products of the phosphatidylinositol 3-kinase (PI3K) reaction. It is well documented that binding of insulin to the membrane receptor stimulates a cascade of phosphorylation events resulting in activation of PI3K. It is likely that PKB/Akt directly increases mTOR activity by phosphorylating mTOR at Ser2448, and it has been hypothesized that this event is a critical point of control in the regulation of protein synthesis.4 It has been postulated that p70S6k signaling may be particularly important in mediating muscle adaptation given that the phosphorylation of this molecule following an exercise bout has been found to be strongly associated with the increase in muscle weight after 6 weeks of chronic stimulation.

The purpose of the present study was to determine whether insulin resistance alters p70S6k signaling after an acute episode of contractile activity. To investigate this possibility, muscle signaling was examined in 12-week-old lean and obese Zucker rats, as it is widely accepted that the insulin resistance exhibited by these animals closely models the development of type 2 diabetes seen in humans.3, 18, 25, 39 We hypothesized that insulin resistance would be associated with differences in how muscle contraction regulates the phosphorylation of the Akt/TOR/p70S6k signaling cascade. To test this hypothesis, the contraction-mediated activation of Akt, mTOR, and p70S6k was assessed either immediately after or 1 or 3 h after a single bout of sciatic nerve stimulation. Taken together, our data suggest that insulin resistance alters contraction-induced p70S6k phosphorylation in skeletal muscle. These findings are consistent with the possibility that insulin resistance alters the way skeletal muscle “senses and responds” to contractile stimuli.


This is the pre-peer reviewed version of the following article: Katta, A., Karkala, S. K., Wu, M., Meduru, S., Desai, D. H., Rice, K. M., & Blough, E. R. (2009). Lean and obese Zucker rats exhibit different patterns of p70s6 kinase regulation in the tibialis anterior muscle in response to high‐force muscle contraction. Muscle & Nerve, 39(4), 503-511,which has been published in final form at

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