Share this article on:

Role of AMP-Activated Protein Kinase in the Molecular Adaptation to Endurance Exercise


Medicine & Science in Sports & Exercise: November 2006 - Volume 38 - Issue 11 - p 1945-1949
doi: 10.1249/01.mss.0000233798.62153.50
SYMPOSIUM: Training for Endurance and Strength: Lessons from Molecular Biology

What are the molecular signals induced by muscle contraction that result in an increase in GLUT4, hexokinase 2, mitochondrial oxidative enzymes, and other adaptations to endurance exercise training? Could repetitive activation of AMP-activated protein kinase (AMPK) be responsible in part? There is substantial evidence for a role of AMPK in inducing adaptations to endurance training: 1) AMPK is activated in response to muscle contraction; 2) chronic chemical activation of AMPK results in increases in GLUT4, hexokinase 2, UCP-3, and citric acid cycle enzymes; 3) muscle contraction and chemical activation of AMPK both result in increases in PGC-1α, a transcriptional coactivator involved in stimulation of mitochondrial biogenesis; and 4) increases in muscle PGC-1α, delta-aminolevulinic acid synthetase, and mitochondrial DNA induced by chronic creatine phosphate depletion in wild-type mice are not observed in dominant-negative AMPK mice. These observations lend credence to the hypothesis that AMPK activation induced by muscle contraction is responsible in part for adaptations to endurance exercise training.

1Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT; and 2Metabolism Section, Joslin Diabetes Center, Boston, MA

Address for correspondence: William W. Winder, Ph.D., 545 WIDB, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602; E-mail:

Submitted for publication December 2005.

Accepted for publication March 2006.

Almost 35 yr have elapsed since the initial discoveries showing that endurance exercise training results in an increase in mitochondrial oxidative enzyme content of skeletal muscle (18). After these initial discoveries, John Holloszy and colleagues and also researchers working in other laboratories carefully characterized the adaptations to chronic exposure of skeletal muscle to exercise that allow it to work at high work rates for longer periods of time without fatigue (18). Increases were observed in citric acid cycle enzymes, proteins of the electron transport chain and oxidative phosphorylation, enzymes of fatty acid and ketone oxidation, proteins involved in glucose uptake and glucose phosphorylation (GLUT4 and hexokinase), myoglobin, and delta-aminolevulinic acid synthetase, a rate-limiting enzyme of heme synthesis. With the dawn of molecular physiology, questions arose regarding the molecular signals induced by skeletal muscle contraction that triggered these adaptations.

Two major signals were suspected of being involved. The first was the repetitive rise in free calcium concentration that occurs, triggering each muscle contraction. In addition to calcium binding to troponin C to initiate muscle contraction, elevated free calcium concentration theoretically would allow binding to other calcium-sensitive proteins, resulting in activation or inactivation. For example, calcium binds to the calmodulin subunit of phosphorylase kinase, resulting in activation of the process of glycogenolysis in contracting muscle. It was deemed possible that other calcium-sensitive proteins could mediate the training adaptations enumerated above. The discovery of calcium-regulated proteins such as the Ca2+/calmodulin-dependent protein kinases (CaMKs) and calcineurin lends credence to this putative signal (9).

The second major signal was thought to be the change in the energy state of the muscle accompanying contraction. This would be manifest by a perturbation of the ATP:ADP:AMP balance. However, proteins were not identified that could monitor the energy charge and signal to downstream targets to mediate the training effects induced by contraction. The discovery and characterization of AMP-activated protein kinase (AMPK) revealed a protein that could monitor changes in the energy charge of the muscle and regulate activities of other proteins by phosphorylation (13,14,48,49). Thus, AMPK became a candidate for initiating adaptive events caused by endurance training. This review will focus on evidence for this hypothesis.

Back to Top | Article Outline


AMPK is a protein composed of three subunits: alpha, beta, and gamma (Fig. 1). The alpha subunit contains the kinase domain and the site for phosphorylation and activation (threonine 172) by the upstream kinase (16). The beta subunit harbors a glycogen-binding domain. The regulatory gamma subunit contains 4 cystathionine-beta-synthase (CBS) domains (1,39). Two of these, which are collectively referred to as a Bateman domain, act as a binding site for 5′-AMP, the activator of AMPK. Binding of an AMP molecule to the first Bateman domain promotes binding of an AMP molecule to the second Bateman domain by increasing the affinity of the second site for AMP. ATP competes with AMP for binding to the Bateman domains and is an inhibitor of AMPK activity (39). The affinity of the sites for AMP is much higher than for ATP (39). Thus, the activating effect is progressive as AMP concentration in the muscle increases during contraction or hypoxia. High muscle glycogen has also been correlated with reduced muscle AMPK activation in response to exercise (13). Taken together, these properties establish AMPK as an energy-sensing enzyme. ATP abundance in the presence of low 5′-AMP concentration and elevated glycogen give rise to a relatively inactive AMPK. A rise in 5′-AMP resulting from the adenylate kinase reaction (2 ADP → ATP + AMP), coupled with declines in ATP and glycogen, will activate AMPK. It should be noted that in skeletal muscle, the total ATP concentration does not decline except at very high work rates, implying that the increase in AMP concentration during contraction is more likely the primary signal for AMPK activation during moderate-intensity work. However, the local subcellular microenvironment of the AMPK must also be considered.



To have activity, AMPK must be phosphorylated at the threonine-172 site on its activation loop by one or more upstream kinases (Winder et al., unpublished observations, 2005) (14), collectively termed AMPK kinases (AMPKKs). A recent important and exciting advance in the field was the finding that a protein complex composed of the tumor suppressor LKB1 (Stk 11) with Ste-related adapter protein (STRAD) and mouse protein 25 (MO25) is the major AMPKK (15,40,52). Evidence from skeletal muscle/cardiac muscle-specific LKB1 knockout experiments shows that LKB1 is an essential component of most of the AMPKK in skeletal muscle (38). A second AMPKK has recently been reported. The beta isoform of CaMK kinase seems to be a viable AMPKK in the absence of LKB1 (17). The role and existence of this signaling pathway has not been clearly defined for skeletal muscle, although it seems reasonable that a Ca2+/calmodulin signal could be involved. An increase in AMP in the muscle makes AMPK a better substrate for the AMPKK and a poorer substrate for phosphatases (13,14).

It is now well established that muscle contraction results in an increase in AMPK activity concomitant with phosphorylation of T-172 on its activation loop (13,32,46,48,49,51). The increase in phosphorylation and AMPK activity is proportional to the work rate (32,35,51). Once activated, AMPK phosphorylates downstream target proteins. In general, ATP-consuming processes such as protein synthesis are inhibited, and ATP-producing processes such as glucose uptake and fat oxidation are stimulated (13,14,48,49). For example, acetyl-CoA carboxylase (ACC) is phosphorylated and inactivated by AMPK (49). This results in a decrease in malonyl-CoA synthesis and relief of inhibition of one of the rate-limiting enzymes of fatty acid oxidation, carnitine palmitoyl transferase 1 (CPT1) (48). Over the long term, AMPK may induce increases in expression of enzymes and proteins involved in ATP production, thus increasing the capacity to generate ATP.

Back to Top | Article Outline


The molecular adaptations to endurance training are designed to increase the capacity of muscle for ATP synthesis. The first evidence that AMPK signaling might mediate these training adaptations came from in vivo experiments on rats. The adenosine analogue, 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR) can be used to chemically activate AMPK in the absence of muscle contraction. This analog of adenosine is taken up by the muscle and phosphorylated by adenosine kinase to produce ZMP, an analog of 5′-AMP. ZMP can activate AMPK similarly to AMP (48). When this chemical is injected into rats, it results in marked activation of skeletal muscle AMPK (19). Daily injection of the drug into rats for 4 d resulted in a large increase in hexokinase activity and GLUT4 protein in the epitrochlearis of rats (19). In addition, the glycogen content of the muscle was increased, which was similar to the supercompensation that occurs during the postexercise period in endurance-trained rats. Ojuka (31) found increases in GLUT4 protein in response to incubation of muscle in vitro, thus demonstrating that the effect was not attributable to nonspecific systemic effects of the AICAR (31). These effects have since been confirmed and extended (8,21,25). Holmes et al. (20) reported that endurance training could increase GLUT4 in dominant-negative AMPK mice and concluded that there are redundant pathways for triggering exercise-induced increases in expression of the GLUT4 gene. The mechanism of the increase in GLUT4 expression in response to AICAR has been investigated. Activated AMPK phosphorylates GLUT4-enhancing factor (GEF), a transcription factor that binds to the GLUT4 promoter (21), increasing the rate of transcription. Injection of mice with AICAR triggers localization of both GEF and MEF2 to the nuclear fraction of the muscle fiber (21).

Another protein that responds early to endurance training of rats (54), but not humans (37), is mitochondrial uncoupling factor 3 (UCP-3). The mRNA for this protein increases in skeletal muscle, even during a single bout of prolonged treadmill running (54). UCP-3 was also observed to increase in response to incubation of muscle with AICAR (34,54) or in EDL muscle in response to injection of rats with AICAR (42). Thus, some of the rapidly occurring effects of training were mimicked in these nonexercising rats or in incubated muscle treated with the AMPK activator.

In addition to GLUT4, hexokinase, and UCP-3, several mitochondrial oxidative enzymes were found to increase in response to chronic treatment of rats with AICAR, including the classical marker of training, citrate synthase, other citric acid cycle enzymes, and cytochrome c (50). The fast-twitch white fibers seemed to be most sensitive to upregulation of mitochondrial oxidative enzymes by AICAR. The magnitude of the increase in AMPK activity was greater in the fast-twitch white fibers than in the fast-twitch red fibers of the quadriceps. The increase in citrate synthase, cytochome c, succinate dehydrogenase, and malate dehydrogenase in different fiber types seemed to be related to the extent of increase in AMPK (50), but the reason for this difference in sensitivity between fiber types is not known.

Endurance training attenuates but does not eliminate the increase in red quadriceps muscle AMPK activity of rats in response to an acute bout of exercise (10). A recent study on human subjects reported complete attenuation of the exercise-induced rise in AMPK activity after 10 d of endurance training (28). In this study, exercise-triggered phosphorylation of ACC, one downstream target, was substantial even after training, indicating that AMPK was activated, although it was not detected in the AMPK assay. It is also possible that another protein kinase that phosphoryates ACC at the same site was activated. Free AMP concentration in the muscle was increased as much as 9- to 10-fold in the trained muscle, thus leaving open the possibility of allosteric activation, which would not be detected in the AMPK assay on immunoprecipitates. Nevertheless, the relative role of AMPK signaling versus calcium-mediated pathways for induction of training adaptations may shift during the course of the training program. It is also likely that more intense work rates are required to activate AMPK as the muscle accumulates additional mitochondrial oxidative enzymes and capacity to generate ATP. Perhaps this is partly why more intense work is needed to elicit improvement as training progresses. It is clear that electrical stimulation via the nerve results in marked activation of AMPK in both nontrained and endurance-trained gastrocnemius muscle of rats (22).

Back to Top | Article Outline


Several factors have been identified as important to the control of mitochondrial biogenesis (27). These include peroxisome proliferator-activated receptor 1 coactivator alpha (PGC-1α), nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2), PPARα, PPARγ, and mitochondrial transcription factor A (Tfam) (2,4,5,11,24,29,30,33,36,45,47,53). Contraction has been demonstrated to increase these transcriptional regulators in muscle. Even one bout of swimming has been reported to increase PGC-1α, NRF-1, and NRF-2 in rat triceps muscle (5). Electrical stimulation of C2C12 myotubes for 4 d results in increases in NRF-1, Tfam, and PGC-1α (24). The contraction-induced increases in PGC-1α can be mimicked in noncontracting muscle cells by chemical activation of AMPK. Incubation of L6E9 myotubes with AICAR to activate AMPK resulted in a significant increase in PGC-1α (24).

Prolonged treatment of mice with β-guanidinopropionic acid (β-GPA) causes a decrease in creatine phosphate and a decrease in the ATP/AMP ratio (6). Under these conditions, muscle AMPK is activated. In wild-type mice, this results in a marked increase in PGC-1α, mitochondrial DNA, and delta-aminolevulinic acid synthetase (ALAS) (55). However, in mice with dominant-negative AMPK, which show no increase in AMPK activity in response to β-GPA feeding, no increases in PGC-1α, mitochondrial DNA, or ALAS are observed (55). These studies provide additional evidence for a role of AMPK in inducing adaptations to endurance exercise training.

A recent study on knockout mice having a deficiency of either the α1 or α2 isoform of AMPK showed no deficiency in training responses to exercise, whereas the response to AICAR was prevented (26). This study demonstrates that chemical AMPK activation in the muscle increases hexokinase and PGC-1α expression, but the study also suggests that AMPK is not necessary for the training effects to occur. The authors pointed out, however, that the presence of either isoform of AMPK could mediate the training adaptations. The double knockout is lethal. Redundancy in control of these adaptations makes elucidation of the essential role of either pathway difficult. Specific inhibitors of AMPK that could be introduced to eliminate AMPK activity over long periods of time are not currently available.

Recent findings suggest that activation of AMPK may be important in regulating the specificity of adaptation to different types of training (e.g., endurance vs resistance training). For example, in isolated rat muscle, electrical stimulation designed to mimic an endurance training bout resulted in increased AMPK phosphorylation and elevated expression of PGC-1α protein and UCP3 mRNA (3). In contrast, concentrations of phosphorylated AMPK, PGC-1α protein, and UCP3 mRNA were not increased after high-frequency electrical stimulation designed to mimic resistance exercise. However, the high-frequency stimulation resulted in elevated protein synthesis and signaling through the translational regulators protein kinase B (PKB), tuberin (TSC2), mammalian target of rapamycin (mTOR), and glycogen synthase kinase 3β (GSK-3β), whereas endurance-type stimulation did not (3). The authors of that study referred to the divergent control of molecular signaling responses to the different forms of exercise as the AMPK-PKB switch. This concept is further substantiated by more direct evidence linking LKB1/AMPK activity to an inhibition of translational signaling (7,12,23).

Back to Top | Article Outline


When LKB1 was first measured in trained and nontrained skeletal muscle, a striking positive correlation was observed between mitochondrial citrate synthase activity in the different muscle types and LKB1 protein determined by Western blot (43). Muscles of endurance-trained rats were found to have significantly increased LKB1 protein content compared with sedentary controls (22,43). MO25 expression was also increased, but STRAD mRNA was not (43). Interestingly enough, even though LKB1 protein expression was increased, the AMPKK activity seemed to be decreased by endurance training (22,43). In a time-course study, LKB1 increased in red quadriceps muscle with a time course similar to citrate synthase and PGC-1α (44). Hexokinase II increased much earlier in the course of the training compared with LKB1. A more recent study demonstrated defects in LKB1/AMPK signaling in the ZDF rat, a model of type 2 diabetes (41). Endurance training induced increases in LKB1, AMPK, hexokinase II, citrate synthase, and PGC-1 in these rats, thus repairing the deficit. LKB1 can be localized to the nucleus and could possibly serve as a regulator of transcription of specific genes, but no firm evidence is available to substantiate this hypothesis. A possible role of LKB1 in inducing expression of specific proteins in the muscle will require use of muscle-specific LKB1 knockout mice.

In summary, evidence has been presented for a role of AMPK signaling in induction of some of the adaptations of skeletal muscle to endurance training. AMPK is phosphorylated and activated in response to muscle contraction. Chemical activation of muscle AMPK with AICAR induces a fiber type-specific increase in hexokinase, GLUT4, and enzymes of the citric acid cycle, which is similar to changes stimulated by endurance training. Transcription factors/coactivators that are important in the regulation of mitochondrial biogenesis and GLUT4 transcription (PGC-1α, NRF-1, NRF-2) have been reported to increase in response to chemical activation of AMPK with AICAR. Increases in factors involved in mitochondrial biogenesis induced by creatine/creatine phosphate depletion are not observed in AMPK dominant-negative mice. Taken together, these observations give credence to the hypothesis that AMPK activation accompanying muscle contraction is one signal responsible for inducing adaptations to endurance training.

Back to Top | Article Outline


1. Adams, J., Z. P. Chen, B. J. Van Denderen, et al. Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci. 13:155-165, 2004.
2. Akimoto, T., S. C. Pohnert, P. Li, et al. Exercise stimulates PGC-1{alpha} transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem. 280:19587-19593, 2005.
3. Atherton, P. J., J. A. Babraj, K. Smith, J. Singh, M. J. Rennie, and H. Wackerhage. Selective activation of AMPK-PGC-1α or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J. 19:786-788, 2005.
4. Baar, K. Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise. Proc. Nutr. Soc. 63:269-273, 2004.
5. Baar, K., A. R. Wende, T. E. Jones, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 16:1879-1886, 2002.
6. Bergeron, R., J. M. Ren, K. S. Cadman, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. 281:E1340-E1346, 2001.
7. Bolster, D. R., S. J. Crozier, S. R. Kimball, and L. S. Jefferson. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 277:23977-23980, 2002.
8. Buhl, E. S., N. Jessen, O. Schmitz, et al. Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes 50:12-17, 2001.
9. Chin, E. R. Role of Ca2+/calmodulin-dependent kinases in skeletal muscle plasticity. J. Appl. Physiol. 99:414-423, 2005.
10. Durante, P. E., K. J. Mustard, S. H. Park, W. W. Winder, and D. G. Hardie. Effects of endurance training on activity and expression of AMP-activated protein kinase isoforms in rat muscles. Am. J. Physiol. 283:E178-E186, 2002.
11. Goto, M., S. Terada, M. Kato, et al. cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem. Biophys. Res. Commun. 274:350-354, 2000.
12. Hahn-Windgassen, A., V. Nogueira, C. C. Chen, J. E. Skeen, N. Sonenberg, and N. Hay. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol Chem. 280:32081-32089, 2005.
13. Hardie, D. G. AMP-activated protein kinase: a key system mediating metabolic responses to exercise. Med. Sci. Sports Exerc. 36:28-34, 2004.
14. Hardie, D. G. New roles for LKB1 → AMPK pathway. Curr. Opin. Cell Biol. 17:167-175, 2005.
15. Hawley, S. A., J. Boudeau, J. L. Reid, et al. Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2:28, 2003.
16. Hawley, S. A., M. Davison, A. Woods, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271:27879-27887, 1996.
17. Hawley, S. A., D. A. Pan, K. J. Mustard, et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2:9-19, 2005.
18. Holloszy, J. O., and F. W. Booth. Biochemical adaptations to endurance exercise in muscle. Annu. Rev. Physiol. 38:273-291, 1976.
19. Holmes, B. F., E. J. Kurth-Kraczek, and W. W. Winder. Chronic activation of 5′-AMP-activated protein kinase increases GLUT4, hexokinase, and glycogen in muscle. J. Appl. Physiol. 87:1990-1995, 1999.
20. Holmes, B. F., D. B. Lang, M. J. Birnbaum, J. Mu, and G. L. Dohm. AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle. Am. J. Physiol. 287:E739-E743, 2004.
21. Holmes, B. F., A. L. Olson, W. W. Winder, and G. L. Dohm. Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase. Am. J. Physiol. 289:E1071-E1076, 2005.
22. Hurst, D., E. B. Taylor, T. D. Cline, et al. AMP-activated protein kinase kinase activity and phosphorylation of AMP-activated protein kinase in contracting muscle of sedentary and endurance trained rats. Am. J. Physiol. 289:E710-E715, 2005.
23. Inoki, K., T. Zhu, and K. L. Guan. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577-590, 2003.
24. Irrcher, I., P. J. Adhihetty, T. Sheehan, A. M. Joseph, and D. A. Hood. PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am. J. Physiol. 284:C1669-C1677, 2003.
25. Jessen, N., R. Pold, E. S. Buhl, L. S. Jensen, O. Schmitz, and S. Lund. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat tissues. J. Appl. Physiol. 94:1373-1379, 2003.
26. Jorgensen, S. B., J. F. Wojtaszewski, B. Viollet, et al. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J. 19:1146-1148, 2005.
27. Kelly, D. P., and R. C. Scarpulla. Transcriptional regulatory circuits controlling mitochondrial biogenesis. Genes Dev. 18:357-368, 2004.
28. McConell, G. K., R. S. Lee-Young, Z. P. Chen, et al. Short-term exercise training in humans reduces AMPK signaling during prolonged exercise independent of muscle glycogen. J. Physiol. 568:665-676, 2005.
29. Michael, L. F., Z. Wu, R. B. Cheatham, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc. Natl. Acad. Sci. U.S.A. 98:3820-3825, 2001.
30. Norrbom, J., C. J. Sundberg, H. Ameln, W. E. Kraus, E. Jansson, and T. Gustafsson. PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J. Appl. Physiol. 96:189-194, 2004.
31. Ojuka, E. O. Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle. Proc. Nutr. Soc. 63:275-278, 2004.
32. Park, S. H., S. R. Gammon, J. D. Knippers, S. R. Paulsen, D. S. Rubink, and W. W. Winder. Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. J. Appl. Physiol. 92:2475-2482, 2002.
33. Puigserver, P., and B. M. Spiegelman. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24:78-90, 2003.
34. Putman, C. T., M. Kiricsi, J. Pearcey, et al. AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J. Physiol. 551:169-178, 2003.
35. Rasmussen, B. B., and W. W. Winder. Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J. Appl. Physiol. 83:1104-1109, 1997.
36. Russell, A. P., J. Feilchenfeldt, S. Schreiber, et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 52:2874-2881, 2003.
37. Russell, A. P., E. Somm, M. Praz, et al. UCP3 protein regulation in human skeletal muscle fibre types I, IIa and IIx is dependent on exercise intensity. J. Physiol. 550:855-861, 2003.
38. Sakamoto, K., A. McCarthy, D. Smith, et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24:1810-1820, 2005.
39. Scott, J. W., S. A. Hawley, K. A. Green, et al. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J. Clin. Invest. 113:274-284, 2004.
40. Shaw, R. J., M. Kosmatka, N. Bardeesy, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. U. S. A. 101:3329-3335, 2004.
41. Sriwijitkamol, A., J. L. Ivy, C. Christ-Roberts, R. A. Defronzo, L. J. Mandarino, and N. Musi. LKB1-AMPK signaling in muscle from obese insulin resistant Zucker rats and effects of training. Am. J. Physiol. 290:E925-E932, 2006.
42. Suwa, M., H. Nakano, and S. Kumagai. Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J. Appl. Physiol. 95:960-968, 2003.
43. Taylor, E. B., D. Hurst, L. J. Greenwood, et al. Endurance training increases LKB1 and MO25 protein but not AMP-activated protein kinase kinase activity in skeletal muscle. Am. J. Physiol. 287:E1082-E1089, 2004.
44. Taylor, E. B., J. D. Lamb, R. W. Hurst, et al. Endurance training increases LKB1 and PGC-1α protein abundance: effects of time and intensity. Am. J. Physiol. 289:E960-E968, 2005.
45. Terada, S., M. Goto, M. Kato, K. Kawanaka, T. Shimokawa, and I. Tabata. Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem. Biophys. Res. Commun. 296:350-354, 2002.
46. Vavvas, D., A. Apazidis, A. K. Saha, et al. Contraction-induced changes in acetyl-CoA carboxylase and 5′-AMP-activated kinase in skeletal muscle. J. Biol. Chem. 272:13255-13261, 1997.
47. Vega, R. B., J. M. Huss, and D. P. Kelly. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20:1868-1876, 2000.
48. Winder, W. W., and D. G. Hardie. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. 277:E1-E10, 1999.
49. Winder, W. W., and D. G. Hardie. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am. J. Physiol. 270:E299-E304, 1996.
50. Winder, W. W., B. F. Holmes, D. S. Rubink, E. B. Jensen, M. Chen, and J. O. Holloszy. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88:2219-2226, 2000.
51. Wojtaszewski, J. F., P. Nielsen, B. F. Hansen, and E. A. Richter. Isoform specific and exercise-intensity-dependent activation of 5′-AMP activated protein kinase in human skeletal muscle. J. Physiol. 528:221-226, 2000.
52. Woods, A., S. R. Johnstone, K. Dickerson, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13:2004-2008, 2003.
53. Wu, Z., P. Puigserver, U. Andersson, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115-124, 1999.
54. Zhou, M., B. Z. Lin, S. Coughlin, G. Vallega, and P. F. Pilch. UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase. Am. J. Physiol. 279:E622-E629, 2000.
55. Zong, H., J. M. Ren, L. H. Young, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl. Acad. Sci. U.S.A. 99:15983-15987, 2002.


©2006The American College of Sports Medicine