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Resistance Training Improves Insulin Signaling and Action in Skeletal Muscle

Yaspelkis, Ben B. III

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Exercise and Sport Sciences Reviews: January 2006 - Volume 34 - Issue 1 - p 42-46
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INTRODUCTION

Skeletal muscle insulin resistance is a hallmark feature of type 2 diabetes, and improvement of insulin action in this tissue is likely to have favorable effects on glycemic control for individuals with diabetes. Aerobic exercise training, which is characterized by a large number of contractions (often many thousand) performed with relatively low force development, has been studied extensively and is well recognized for its beneficial effects on skeletal muscle glucose metabolism. In contrast, the effects of resistance training, which typically consists of a small number of contractions (often fewer than 10–20) with relatively high force development on skeletal muscle glucose metabolism has not received as much attention. The conventional thinking has been that these types of training induce very different adaptations, but both types of training can improve insulin action and glucoregulation, although it is not clear if these methods of training achieve this same outcome by identical mechanisms. A body of literature exists indicating that resistance training can improve whole body carbohydrate metabolism and insulin action (i.e., activation of the insulin signaling cascade and glucose transporter system), and it has been suggested that these improvements are the result of increases in lean body mass. Miller et al. (9) evaluated the effects of strength training in young males after a 10-wk resistance training program and observed, posttraining compared with pretraining, that the glucose response during an oral glucose tolerance test was not altered, but that less insulin was required to achieve the same effect on plasma glucose concentration, suggesting that insulin sensitivity was improved. These investigators also reported that the decreased insulin response after the resistance training program was correlated (r = 0.89) with increased lean body mass, leading to the conclusion that because muscle mass was greater and because skeletal muscle is an important site for insulin-stimulated glucose disposal, that the greater muscle mass would be able to clear a greater amount of blood glucose.

The high correlation between changes in lean body mass (which is assumed to be muscle) and the change in insulin during an oral glucose tolerance test sometimes has been misinterpreted to mean that the effects of resistance training on insulin sensitivity are largely or entirely attributable to an increase in muscle mass. What is assumed is that qualitative changes in muscle are irrelevant for the improved insulin action with resistance exercise training. However, a high correlation does not necessarily prove that a cause-and-effect relationship exists. It has been shown that the magnitude of increased insulin-stimulated glucose disposal outstrips the magnitude of changes in muscle mass found with typical resistance-training protocols (8), which argues strongly for changes in the quality of the muscle (as opposed solely to quantity of muscle) being important for improving skeletal muscle insulin sensitivity. The question, then, is what are the changes in the quality of the muscle that are important for enhancing insulin sensitivity in response to resistance exercise training?

DO THE QUALITATIVE CHANGES IN MUSCLE WITH RESISTANCE EXERCISE INCLUDE ALTERED INSULIN SIGNALING, GLUT-4 ABUNDANCE, OR BOTH?

In our initial investigation (13), we decided to use a rodent model of resistance training because we believed that this would enable us to evaluate more effectively the effects of the resistance exercise on skeletal muscle glucose metabolism. In addition, we also included an aerobic training group so that specific adaptations on skeletal muscle glucose metabolism that occur in response to resistance, aerobic exercise training, or both could be characterized. Resistance-trained rats performed three sets of 10 repetitions at 75% of 1 repetition maximum (1-RM) three times weekly for 12 wk in a squat apparatus modeled on a unit described by Tamaki et al. (12). The sets and repetitions that the animals performed were intended to parallel closely the general recommendations for humans because the optimal resistance training program for rodents has yet to be established. Aerobically trained animals ran on a motor-driven treadmill (32 m·min−1, 15% grade) 3 d·wk−1 for 12 wk. At the end of the 12-wk training period, all animals were subjected to hindlimb perfusion, which allows for the measurement of the metabolism of the hindlimb musculature using an experimentally prepared media that is infused into a major artery (i.e., abdominal aorta) and collected through a major vein (i.e., inferior vena cava). Perfusions were performed 36–40 h after the last exercise bout to ensure that the observations were a function of training and not a result of an acute bout of exercise.

When compared with nonexercised control animals, resistance-trained rats had increased insulin-stimulated glucose uptake, and the resistance and aerobic training programs were equally effective in increasing rates of insulin-stimulated hindlimb glucose uptake (Fig. 1). Hindlimb glucose uptake, calculated based on the product of arteriovenous glucose differences and perfusate flow rates, represents the net disposal of glucose by hindlimb tissues, which consist predominantly of skeletal muscle. The glucose uptake rate is dependent on the rate of facilitated diffusion of glucose across the cell surface membranes (glucose transport) and subsequent glucose metabolism inside the cell. To evaluate the training effects in specific muscles, rates of insulin-stimulated glucose transport were assessed based on the accumulation of a nonmetabolizable sugar (3-O-methylglucose) in several muscles. This measurement represents the rate at which glucose is transported across the plasma membrane independent of intracellular glucose metabolism. Aerobically trained animals had rates of insulin-stimulated glucose transport that were elevated in the lower leg muscles used primarily for running (i.e., soleus, plantaris, red gastrocnemius), whereas in the resistance-trained animals, rates of insulin-stimulated glucose transport were elevated in the upper leg muscles that were relied on for performing squats (i.e., red and white quadriceps).

Figure 1.
Figure 1.:
Glucose uptake in hindlimbs of sedentary, aerobically trained, and resistance-trained rats during perfusion with 8 mM glucose and 500 μU·mL−1 insulin. *Significantly different from sedentary (P < 0.05). (Reprinted from Yaspelkis, B.B. III, M.K. Singh, B. Trevino, A.D. Krisan, and D.E. Collins. Resistance training increases skeletal muscle glucose uptake and transport. Acta Physiol. Scand. 175:315–323, 2002. Copyright © 2002 Scandinavian Physiological Society. Used with permission.)

Of note, the improvements in glucose transport in the resistance-trained animals occurred independent of a significant increase in hindlimb muscle mass. That is, resistance training did not need to induce increases in skeletal muscle mass to improve skeletal muscle glucose metabolism. Rather, the training-induced improvements in insulin-stimulated glucose transport in both the aerobically and resistance-trained animals in part were the result of the primary insulin- and contraction-sensitive glucose transporter isoform expressed in skeletal muscle, GLUT-4, being elevated. Specifically, GLUT-4 protein concentration was increased in the lower leg muscles of the aerobically trained animals (i.e., soleus, plantaris, gastrocnemius), whereas in the resistance-trained animals, GLUT-4 protein concentration was elevated in the upper leg muscles (i.e., quadriceps).

CAN RESISTANCE TRAINING AFFECT INSULIN SIGNALING AND IMPROVE INSULIN RESISTANCE IN SKELETAL MUSCLE?

Although the increased rates of insulin-stimulated glucose transport in resistance-trained skeletal muscle were attributed to an increased GLUT-4 protein concentration (13), it is possible that resistance training also may be capable of altering components of the insulin signaling cascade, which may contribute further to enhancing the quality of the resistance-trained skeletal muscle. The translocation of GLUT-4–containing vesicles from their intracellular storage location to cell surface membranes is a complex, multistep process (Fig. 2). Insulin signaling is initiated by the binding of insulin to its receptor. As soon as insulin is bound to the receptor, tyrosine residues in the β subunit of the receptor are autophosphorylated, which stimulates the kinase activity of the receptor, resulting in phosphorylation of insulin receptor substrates (IRSs). When IRS-1 is activated, the regulatory subunit (p85) of phosphatidylinositol (PI) 3-kinase docks with IRS-1, thereby activating PI 3-kinase via the p110 catalytic subunit, resulting in the activation of phosphatidylinositol-dependent protein kinase. Phosphatidylinositol-dependent protein kinase, in turn, phosphorylates the serine/threonine kinases Akt and atypical protein kinase C (aPKC) ζ/λ, which when activated have been implicated as potential key signals linking activation of PI 3-kinase to glucose transporter translocation.

Figure 2.
Figure 2.:
Insulin signaling and glucose transport in (a) untrained and (b) resistance-trained rodent skeletal muscle (bold lines represent increased activation of PI-3, aPKC-ζ/λ, and Akt and increased GLUT-4 protein concentration). See text for a complete description of the model.

In a follow-up investigation, we determined whether resistance training could improve insulin signaling in normal and insulin-resistant skeletal muscle (7). We had used the high fat–fed (26% carbohydrate, 59% fat, and 15% protein) rodent model in several previous investigations and reported that insulin-stimulated IRS-1–associated PI-3 kinase activity, total GLUT-4 protein concentration, and insulin-stimulated plasma membrane-associated GLUT-4 protein concentration were reduced in this model when compared with rodents that were fed a normal (63% carbohydrate, 17% fat, and 20% protein) diet (11,14). Thus, we believed that this model could be useful in determining if resistance training might reverse skeletal muscle insulin resistance. The frequency and intensity of the resistance training was similar to our previous investigation (13), and animals remained on either their normal or high-fat diet throughout the training. However, the training apparatus was redesigned such that the training the rodents performed more closely resembled a traditional squat movement (Fig. 3).

Figure 3.
Figure 3.:
Resistance-training apparatus. (Reprinted from Krisan, A.D., D.E. Collins, A.M. Crain, C.C. Kwong, M.K. Singh, J.R. Bernard, and B.B. Yaspelkis III. Resistance training enhances components of the insulin signaling cascade in normal and high fat–fed rodent skeletal muscle. J. Appl. Physiol. 96:1691–1700, 2004. Copyright © 2004 American Physiological Society. Used with permission.)

In agreement with our initial investigation, resistance training increased insulin-stimulated rates of glucose uptake and transport (Table) and skeletal muscle GLUT-4 protein concentration (Fig. 4) in normal rodent skeletal muscle in the absence of significant alterations in muscle mass. Of interest, although chronic resistance training did not alter IRS-1, Akt 1/2, aPKC ζ, or aPKC λ protein concentration in normal rodent skeletal muscle (7), the activation of the insulin signaling cascade was enhanced. Specifically, insulin-stimulated IRS-1–associated PI-3 kinase activity (Fig. 5a) and aPKC-ζ/λ activity (Fig. 5c), but not Akt 1/2 activity (Fig. 5b), were greater in the resistance-trained muscle. These observations clearly showed that resistance training could alter components of the insulin signaling cascade in skeletal muscle and supported the contention that rates of glucose transport are elevated in resistance-trained skeletal muscle because of improvements in muscle quality.

TABLE
TABLE:
Insulin-stimulated total hindlimb glucose uptake and red quadriceps glucose transport
Figure 4.
Figure 4.:
Total GLUT-4 protein concentration in the red quadriceps (RQ). Norm-Sed, normal diet sedentary; Norm-RT, normal diet, resistance trained; HF-Sed, high-fat diet, sedentary; HF-RT, high-fat diet, resistance trained. *Significantly different from Norm-Sed (P < 0.05). †Significantly different from HF-Sed (P < 0.05). #Significantly different from HF-RT (P < 0.05). Data from (7).
Figure 5.
Figure 5.:
Insulin-stimulated (a) IRS-1 associated PI3-kinase activity, (b) Akt kinase activity, and (c) aPKC-ζ/λ kinase activity in red quadriceps (RQ). Norm-Sed, normal diet sedentary; Norm-RT, normal diet, resistance trained; HF-Sed, high-fat diet, sedentary; HF-RT, high-fat diet, resistance trained. *Significantly different from Norm-Sed (P < 0.05). †Significantly different from HF-Sed (P < 0.05). #Significantly different from HF-RT (P < 0.05). Data from (7).

Although it was not predictable that resistance training could enhance insulin signaling in insulin-resistant skeletal muscle, our observation in normal skeletal muscle provided the possibility that resistance training may be capable of reversing the deleterious effects of high-fat feeding on skeletal muscle insulin signaling. Consistent with the literature, we observed that high-fat feeding reduced insulin-stimulated rates of glucose uptake and transport in rodent skeletal muscle (Table). Although the high-fat diet did not affect the skeletal muscle concentration of IRS-1, Akt 1/2, aPKC ζ, or aPKC λ, the activities of PI-3 kinase (Fig. 5a), Akt 1/2 (Fig. 5b), and aPKC-ζ/λ (Fig. 5c), as well as total GLUT-4 protein concentration, were reduced (Fig. 4). After 12 wk of resistance training, insulin-stimulated rates of hindlimb glucose uptake and red quadriceps glucose transport not only were reversed, but also the rates of glucose transport in the red quadriceps were as high as that of normal diet animals that also performed resistance training. Resistance training did not alter IRS-1, Akt 1/2, aPKC ζ, or aPKC λ protein concentration in the high fat–fed rodents. Rather, chronic resistance training reversed the effects of high-fat diet–induced insulin resistance by normalizing or enhancing, or both, insulin-stimulated PI-3 kinase activity (Fig. 5a), Akt activity (Fig. 5b), aPKC-ζ/λ activity (Fig. 5c), and total GLUT-4 protein concentration (Fig. 4).

It seems that similar training adaptations occur in response to resistance training in humans. Holten et al. (6) had type 2 diabetic patients perform a strength training program 3 d·wk−1 for 6 wk on one leg while the other leg remained untrained. The resistance training program did not significantly increase skeletal muscle mass, but glucose uptake was increased in the trained leg. The improvements in skeletal muscle carbohydrate metabolism were attributed to the resistance training increasing skeletal muscle GLUT-4, insulin receptor, Akt 1/2, and glycogen synthase protein concentration. It is not readily apparent why Akt 1/2 is elevated in human but not rodent skeletal muscle in response to resistance training, but it may be related to the volume of resistance training, because the humans performed multiple leg exercises (i.e., leg press, knee extension, and leg curl) in training sessions lasting up to 30 min, whereas the rodents used only one exercise (i.e., squats) performed in three sets of 10 repetitions. Regardless of these differences, improvements in response to resistance training in type 2 diabetic humans were the result of qualitative changes of the skeletal muscle.

It seems that chronic resistance training by rats improves insulin-stimulated glucose transport primarily by enhancing the activation of PI-3 kinase, aPKC-ζ/λ, and Akt, and increasing total GLUT-4 protein concentration (Fig. 2b). Resistance training also seems to increase insulin receptor and Akt 1/2 protein concentration in type 2 diabetic human skeletal muscle. Thus, because components of the insulin signaling cascade are enhanced and GLUT-4 protein concentration is increased, more GLUT-4 is likely translocated to the plasma membrane in response to insulin, leading to increased rates of glucose transport in resistance-trained skeletal muscle (Fig. 2b).

INCREASED GLUT-4 PROTEIN CONTENT IS DISSOCIATED FROM OXIDATIVE CAPACITY IN RESISTANCE TRAINED MUSCLE

The effects of aerobic training on rates of insulin-stimulated glucose transport, GLUT-4 protein concentration, and oxidative capacity in skeletal muscle are well characterized. GLUT-4 protein concentration is related to the oxidative capacity of the skeletal muscle, rates of insulin stimulated glucose transport are related to the GLUT-4 protein concentration of the skeletal muscle, and aerobic exercise training results in a coordinated upregulation of these variables (1,2,4). In contrast, resistance training increases rates of insulin-stimulated glucose transport and GLUT-4 protein concentration independent of changes in oxidative capacity in both rodent (7,13) and human (6) skeletal muscle. Why this difference exists between aerobically and resistance-trained skeletal muscle is difficult to reconcile based on the purported exercise signals. Elevated 5′-AMP activated protein kinase and cytosolic Ca2+ concentration are believed to be important signals leading to an increase in skeletal muscle oxidative capacity (5,10). However, in addition to increasing skeletal muscle GLUT-4 protein concentration, 5′-AMP activated protein kinase and cytosolic Ca2+ also increase skeletal muscle oxidative capacity. Because resistance training increases GLUT-4 protein concentration independent from alterations in the oxidative capacity of the skeletal muscle, further investigation is warranted to determine if the exercise signal that induces improvements in skeletal muscle glucose metabolism in response to resistance training differs from that of aerobic exercise training.

CONCLUSIONS

It has been reported that resistance exercise training can improve insulin sensitivity and can allow for blood glucose levels to be better managed (i.e., improved glycemic control) in adults with type 2 diabetes (3). The results from our studies indicate, at least in rodents, that changes in key insulin signaling steps and GLUT-4 abundance are likely mechanisms that contribute to these benefits of resistance exercise training. In addition, it should be noted that these training-induced alterations can occur independent of significant increases in skeletal muscle mass.

Acknowledgment

The work cited in this review was supported by the National Institutes of Health (grants GM-48680, GM-08395, and DK-57625).

References

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Keywords:

exercise training; insulin resistance; GLUT-4; glucose transport; phosphatidylinositol 3-kinase; Akt; atypical protein kinase C ζ/λ

©2006 The American College of Sports Medicine