Medicine & Science in Sports & Exercise:
SYMPOSIUM: Training for Endurance and Strength: Lessons from Molecular Biology
Training for Endurance and Strength: Lessons from Cell Signaling
Division of Molecular Physiology, University of Dundee, Dundee, UNITED KINGDOM
Address for correspondence: Keith Baar, Ph.D., Functional Molecular Biology Lab, Division of Molecular Physiology, University of Dundee, MSI/WTB Dow Street, Dundee DD1 5EH, UK; E-mail: email@example.com.
Submitted for publication December 2005.
Accepted for publication April 2006.
The classic work of Hickson demonstrated that training for both strength and endurance at the same time results in less adaptation compared with training for either one alone: this has been described as the concurrent training effect. Generally, resistance exercise results in an increase in muscle mass, and endurance exercise results in an increase in muscle capillary density, mitochondrial protein, fatty acid-oxidation enzymes, and more metabolically efficient forms of contractile and regulatory proteins. In the 25 yr since Hickson's initial description, there have been a number of important advances in the understanding of the molecular regulation of muscle's adaptation to exercise that may enable explanation of this phenomenon at the molecular level. As will be described in depth in the following four papers, two serine/threonine protein kinases in particular play a particularly important role in this process. Protein kinase B/Akt can both activate protein synthesis and decrease protein breakdown, thus leading to hypertrophy, and AMP-activated protein kinase can increase mitochondrial protein, glucose transport, and a number of other factors that result in an endurance phenotype. Not only are PKB and AMPK central to the generation of the resistance and endurance phenotypes, they also block each other's downstream signaling. The consequence of these interactions is a direct molecular blockade hindering the development of the concurrent training phenotype. A better understanding of the activation of these molecular pathways after exercise and how they interact will allow development of better training programs to maximize both strength and endurance.
While completing his postdoctoral fellowship at Washington University in St. Louis, Dr. Robert Hickson noticed that the runs he did with his mentor, Dr. John Holloszy, seemed to cause him to lose muscle mass. The two men agreed that this should be the first thing that Dr. Hickson studied when he took up a position of his own. In 1980, Dr. Hickson published the first experimental demonstration of the specificity of training (20). In this article he showed what athletes and coaches had believed for years: training to improve strength was negatively affected by concurrent endurance exercise. At the time, very little was known about how resistance training increased muscle mass or how endurance exercise increased mitochondrial density, so Hickson could only hypothesize as to how the two processes interacted. In the intervening 25 yr, the mechanisms underlying muscle adaptation to exercise have been better elucidated, and we can now propose a model to explain the concurrent training effect. The articles that follow are the proceedings of a symposium entitled "Training for Endurance and Strength: Lessons from Molecular Biology," which was part of the ACSM annual meeting in Nashville in 2005. This paper will introduce many of the molecular players and provide the background for the specific papers that follow.
Exercise is a general term used to describe a wide variety of activities and sports that can be classified into three subtypes: endurance, resistance, and patterned movements. Patterned movement exercises deal largely with a motor program in the central nervous system and result in relatively small biochemical changes in muscle, whereas resistance and endurance exercise have a profound impact on muscle phenotype. In the past 2500 yr, many myths and a great deal of scientific research have focused on the phenotypic and functional changes of muscle in response to exercise. A classic fable concerns Milo of Crotona, the Greek farmer who would do his morning exercises every day with a calf draped across his shoulders. As the calf grew, so did Milo's strength. At the time of the Olympiad, he could complete his exercises with what had become a full-grown bull on his shoulders, making his strength unparalleled. The theory described in this fable has been termed the overload principle: muscle hypertrophy occurs as a result of systematic and progressive exercise of sufficient frequency, intensity, and duration, causing adaptation.
The overload principle has been thoroughly investigated during the past 100 yr. The conclusion from these studies is that exercise of a short duration and high intensity produces skeletal muscle hypertrophy (10). Duration denotes the length of time that work is occurring; intensity denotes the resistance or tension across the muscle. For muscle growth, duration is kept under a minute per exercise, and tension is the maximum that will allow completion of the exercise. The results of this type of high-resistance training include increases in wet mass (6), fiber cross-sectional area (51), protein content (56), RNA content (56), and the capacity to generate force (12,28).
In contrast, decreasing the intensity and increasing the duration of exercise results in different adaptations within the muscle. This type of exercise results in an endurance phenotype characterized by increased mitochondrial mass (21), increased oxidative enzymes (23), decreased glycolytic enzymes (38), increased slow contractile and regulatory proteins (38,49), and a decrease in fast-fiber area (47).
Concurrent training (training for both strength and endurance) results in decreased strength gains, suggesting that, in some way, the endurance training limits skeletal muscle growth (20).
As described above, a change in muscle phenotype is the result of repeated bouts of exercise. Although each individual bout of exercise is necessary, it alone is not sufficient to alter muscle phenotype. After a single bout of exercise, there is a transient alteration within muscle that, when repeated at sufficient frequency, produces a new steady state within skeletal muscle. This acute effect could be the result of an alteration in the metabolic state of muscle, the activation of a mechanosensor within the muscle, or the local effect an autocrine factor such as IGF-1 or mechano growth factor that is released by muscle cells in response to exercise (17,55,58).
The primary acute response to resistance exercise is an increase in the rate of protein synthesis. In humans, a single bout of resistance exercise increases the rate of protein synthesis by 50% at 4 h and by 115% at 24 h before returning to basal again by 36 h (32). This increase in protein synthesis occurs without a change in the RNA content, suggesting that the changes in protein synthesis after resistance exercise are the result of an increase in the amount of protein synthesized per molecule of RNA (18). This has been confirmed in isolated muscles from chickens (30) and rabbits (45), in vivo in rat muscle (56), and in cell free extracts (18). Interestingly, rapamycin, a bacterial macrolide that specifically inhibits mTOR when bound to raptor (see below), blocks the resistance exercise-stimulated increase in protein synthesis, even though it has little effect on basal protein synthesis (29). This suggests that basal and growth-related synthesis are controlled by different mechanisms and that mTOR is essential for the increase in protein synthesis after resistance exercise.
The rate of protein synthesis is regulated primarily at the initiation phase by a number of proteins that are controlled by posttranslational modification (9). Three key proteins expressed in all cell types (eukaryotic initiation factor 2 (eIF2), 4E binding proteins (4E-BP), and the 70-kDa S6 protein kinase (S6K1)) are believed to be the primary controls of initiation. eIF2 is thought to regulate general protein synthesis, and 4E-BP and S6K1 are believed to control growth-related protein synthesis (34). As described below, the activity of all three proteins requires mTOR and/or PDK1 and is modulated by exercise.
PDK1 is a constitutively active protein kinase whose downstream signaling is controlled by its subcellular localization and/or the conformation of its targets (33). mTOR, on the other hand, is activated by a complex series of phosphorylation events. To add to the complexity, mTOR exists in two protein complexes (57). TOR complex 1 (TORC1) consists of mTOR, the G-protein beta-like protein (GβL/LST8) and raptor and is responsible for cell growth, whereas TORC2 contains mTOR, GβL, and rictor and is important in cytoskeletal organization (57). The different function of the two complexes is dictated by the ability of raptor or rictor to bind to downstream targets (4). Three mechanisms have been identified for the activation of TORC1 and its downstream targets (Fig. 1). The most widely studied mechanism of TORC1 activation is growth factor stimulation, but TORC1 can also be activated by amino acid stimulation and Vps34 mediated autophagy. The growth factor-stimulated pathway works through phosphoinositol 3-kinase (PI 3-kinase)-mediated production of phosphoinositol 3,4,5 tris phosphate (PIP3) at the cell membrane (33). PIP3 increases the protein kinase B/akt (PKB) and PDK1 at the membrane by interaction with the pleckstrin homology domains (3,33). When colocalized at the membrane, PKB is phosphorylated and activated by successive phosphorylation on Thr308 by PDK1 (33) and on Ser473 by TORC2 (43). Active PKB is then able to phosphorylate its targets, which include glycogen synthase kinase 3β (GSK3β) (13), the forkhead (FOXO) transcription factors (42,48), and the GTPase-activating protein TSC2 (Tuberin) (25). PKB-dependent phosphorylation inactivates GSK3β, FOXO, and TSC2. Inactivation of GSK3β increases the rate of translation by increasing eIF2B activity (54), phosphorylation of FOXO removes it from the nucleus and decreases FOXO-dependent transcription of atrogenes (42,48), and phosphorylation of TSC2 blocks its GTPase activity towards the Ras-like protein, Rheb, keeping it in the active GTP-bound form (24). GTP-bound Rheb stimulates the activation of TORC1 and, through interactions with raptor, mTOR phosphorylates its downstream targets, S6K1 and 4E-BP (24,44).
FIGURE 1-Representat...Image Tools
The second mechanism of activation of TORC1 is observed in the case of nutrient deprivation and refeeding of amino acids. The refeeding of amino acids inactivates TSC1/2 in an unidentified PKB-independent manner (50). The inactivation of TSC2 leads to more GTP-bound Rheb, activating mTOR and its downstream targets as described above. The most recently identified mechanism for activating TORC1 is through the class III PI 3-kinase Vps34 (11), which is required for autophagy (protein breakdown within the cell). Vps34 overexpression can activate TORC1 in kidney cells, and using an antibody to block Vps34 activation decreases insulin-stimulated mTOR activity (11). One important role of Vps34 may be to sense the availability of amino acids within the cell, because its activity decreases when amino acids are withheld. However, whether Vps34 is involved in exercise signalling has yet to be addressed.
We and others have shown that muscle strain or resistance exercise can transiently activate mTOR (37), PKB (36), S6K (6), inactivate GSK3β (53), and increase eIF2B activity (15,29). Furthermore, rapamycin treatment has been shown to prevent skeletal muscle hypertrophy in mice, indicating that TORC1 activity is required for skeletal muscle enlargement (8). However, it is still unclear which TORC1 targets are important in the development of hypertrophy. Also unclear is whether the activation of TORC1 is the result of PKB activation, stimulation of the amino acid or autophagy pathways, or an altogether separate mechanosensory pathway. Overexpression of PKB in vitro in muscle cells (40) and in mice results in an increase in muscle size (8), suggesting that the activation of PKB after resistance exercise is sufficient for muscle hypertrophy.
During exercise of long duration, there is a progressive increase in the AMP:ATP ratio and the level of intracellular free calcium (22). Both of these intracellular changes are signals for muscle adaptation. The rise in the AMP:ATP ratio increases the amount of AMP bound to AMPK (19). This causes a conformational change in AMPK that makes it a better substrate for its constitutively active upstream kinase LKB1, resulting in an increase in AMPK activity after endurance exercise (55). The rise in intracellular free calcium activates a number of calcium-sensitive signaling molecules, including the calcium- and calmodulin-activated protein kinase (CamK) (16). Active AMPK and CamK are able to phosphorylate histone deacetylases (HDAC) and permit myocyte-enhancing factor (MEF) 2 binding to the promoter of PGC-1α (14). MEF2 binding to the PGC-1α promoter increases the expression of this critical mitochondrial-regulating gene. PGC-1α coregulates the expression of respiratory genes, mitochondrial transcription factor A, GLUT4 (35), the fatty acid-oxidation enzymes (14), and, possibly, the slow myosin heavy chain (5,31). Because all of these factors also change with endurance exercise, it is not surprising that this type of exercise has been shown to increase both PGC-1α mRNA (1,2,7) and protein (27).
Recent advances have provided possible molecular targets that may explain the concurrent training effect identified by Hickson (20). First, TSC2 can be phosphorylated and activated by AMPK (26). Activation of TSC2 by AMPK is dominant over PKB-mediated inactivation and leads to the inactivation of mTOR and a decrease in the rate of protein synthesis (26). The hypothesis that concurrent high levels of AMPK activity would reduce hypertrophy after resistance exercise was supported by experiments in old animals that underwent overload hypertrophy. A higher level of AMPK activity correlated with diminished hypertrophy in the old animals (52). However, a muscle-specific knockout of LKB1, the enzyme that activates AMP kinase, does not induce an increase in cell size (41), as would be expected from this hypothesis. For this reason, the role of AMPK in preventing muscle growth remains uncertain.
Another potentially interesting mechanism to explain the concurrent training effect was suggested by recent work by Southgate and colleagues (46). This study demonstrated that PKB could control PGC-1α expression by phosphorylating FOXO1 and removing it from the nucleus. This suggests that when PKB is activated after resistance exercise, in the process of decreasing the expression of atrogenes and attenuating the increase in protein degradation (39,42,48), PKB might prevent mitochondrial biogenesis. However, in his original paper on the concurrent training effect, Hickson (20) did not observe that resistance training impaired endurance capacity, only that endurance training impaired strength gains. Whether there is an effect of strength training on decreasing mitochondrial biogenesis has yet to be determined.
As complex as the molecular interactions after exercise are, they are still far from complete. Even so, we can already see how understanding these pathways can improve the way that we combine endurance and resistance training. The papers that follow focus on how these pathways are activated by exercise and diet and how they interact to alter skeletal muscle phenotype. Each paper summarizes the most recent work in the area, including the role of AMP kinase in the molecular adaptation to endurance exercise (Winder), mTOR signaling and the molecular adaptation to resistance exercise (Bodine), the interaction between the AMP kinase and mTOR signaling pathways (Kimball), and how to use this information for improving training for strength and endurance (Nader). Although we have progressed from the seminal work of Dr. Hickson, there remain significant challenges to completely understand how exercise alters skeletal muscle phenotype.
1. Akimoto, T., S. C. Pohnert, P. Li, et al. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem.
2. Akimoto, T., B. S. Sorg, and Z. Yan. Real-time imaging of peroxisome proliferator-activated receptor-gamma coactivator-1alpha promoter activity in skeletal muscles of living mice. Am. J. Physiol. Cell Physiol.
3. Alessi, D. R., and P. Cohen. Mechanism of activation and function of protein kinase B. Curr. Opin. Genet. Dev.
4. Ali, S. M., and D. M. Sabatini. Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J. Biol. Chem.
5. Baar, K. Involvement of PPARgamma co-activator-1, nuclear respiratory factors 1 and 2, and PPARalpha in the adaptive response to endurance exercise. Proc. Nutr. Soc.
6. Baar, K., and K. Esser. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am. J. Physiol.
7. 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.
8. Bodine, S. C., T. N. Stitt, M. Gonzalez, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat. Cell Biol.
9. Bolster, D. R., L. S. Jefferson, and S. R. Kimball. Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling. Proc. Nutr. Soc.
10. Booth, F. W., and D. B. Thomason. Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol. Rev.
11. Byfield, M. P., J. T. Murray, and J. M. Backer. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem.
12. Colliander, E. B., and P. A. Tesch. Effects of eccentric and concentric muscle actions in resistance training. Acta. Physiol. Scand.
13. Cross, D. A., D. R. Alessi, P. Cohen, M. Andjelkovich, and B. A. Hemmings. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature
14. Czubryt, M. P., J. McAnally, G. I. Fishman, and E. N. Olson. Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc. Natl. Acad. Sci. U. S. A.
15. Farrell, P. A., M. J. Fedele, T. C. Vary, S. R. Kimball, C. H. Lang, and L. S. Jefferson. Regulation of protein synthesis after acute resistance exercise in diabetic rats. Am. J. Physiol.
16. Fluck, M., M. N. Waxham, M. T. Hamilton, and F. W. Booth. Skeletal muscle Ca(2+)-independent kinase activity increases during either hypertrophy or running. J. Appl. Physiol.
17. Goldspink, G. Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload. J. Anat.
18. Hamosch, M., M. Lesch, J. Baron, and S. Kaufman. Enhanced protein synthesis in a cell-free system from hypertrophied skeletal muscle. Science
19. Hardie, D. G., and K. Sakamoto. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda)
20. Hickson, R. C. Interference of strength development by simultaneously training for strength and endurance. Eur. J. Appl. Physiol. Occup. Physiol.
21. Holloszy, J. O. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem.
22. Holloszy, J. O. Exercise-induced increase in muscle insulin sensitivity. J. Appl. Physiol.
23. Holloszy, J. O., L. B. Oscai, I. J. Don, and P. A. Mole. Mitochondrial citric acid cycle and related enzymes: adaptive response to exercise. Biochem. Biophys. Res. Commun.
24. Inoki, K., Y. Li, T. Xu, and K. L. Guan. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev.
25. Inoki, K., Y. Li, T. Zhu, J. Wu, and K. L. Guan. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol.
26. Inoki, K., T. Zhu, and K. L. Guan. TSC2 mediates cellular energy response to control cell growth and survival. Cell
27. 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. Cell Physiol.
28. Jones, D. A., and O. M. Rutherford. Human muscle strength training: the effects of three different regimens and the nature of the resultant changes. J. Physiol.
29. Kubica, N., D. R. Bolster, P. A. Farrell, S. R. Kimball, and L. S. Jefferson. Resistance exercise increases muscle protein synthesis and translation of eukaryotic initiation factor 2Bepsilon mRNA in a mammalian target of rapamycin-dependent manner. J. Biol. Chem.
30. Laurent, G. J., M. P. Sparrow, and D. J. Millward. Turnover of muscle protein in the fowl. Changes in rates of protein synthesis and breakdown during hypertrophy of the anterior and posterior latissimus dorsi muscles. Biochem. J.
31. Lin, J., H. Wu, P. T. Tarr, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature
32. MacDougall, J. D., M. J. Gibala, M. A. Tarnopolsky, J. R. MacDonald, S. A. Interisano, and K. E. Yarasheski. The time course for elevated muscle protein synthesis following heavy resistance exercise. Can. J. Appl. Physiol.
33. McManus, E. J., B. J. Collins, P. R. Ashby, et al. The in vivo role of PtdIns(3,4,5)P(3) binding to PDK1 PH domain defined by knockin mutation. EMBO J.
34. Mendez, R., G. Kollmorgen, M. F. White, and R. E. Rhoads. Requirement of protein kinase C zeta for stimulation of protein synthesis by insulin. Mol. Cell Biol.
35. 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.
36. Nader, G. A., and K. A. Esser. Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. J. Appl. Physiol.
37. Parkington, J. D., A. P. Siebert, N. K. LeBrasseur, and R. A. Fielding. Differential activation of mTOR signaling by contractile activity in skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol.
38. Pette, D., and C. Heilmann. Transformation of morphological, functional and metabolic properties of fast-twitch muscle as induced by long-term electrical stimulation. Basic. Res. Cardiol.
39. Phillips, S. M., K. D. Tipton, A. A. Ferrando, and R. R. Wolfe. Resistance training reduces the acute exercise-induced increase in muscle protein turnover. Am. J. Physiol.
40. Rommel, C., S. C. Bodine, B. A. Clarke, et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat. Cell Biol.
41. Sakamoto, K., A. McCarthy, D. Smith, et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J.
42. Sandri, M., C. Sandri, A. Gilbert, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell
43. Sarbassov, D. D., D. A. Guertin, S. M. Ali, and D. M. Sabatini. Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science
44. Schalm, S. S., D. C. Fingar, D. M. Sabatini, and J. Blenis. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol.
45. Smith, R. H., R. M. Palmer, and P. J. Reeds. Protein synthesis in isolated rabbit forelimb muscles. The possible role of metabolites of arachidonic acid in the response to intermittent stretching. Biochem. J.
46. Southgate, R. J., C. R. Bruce, A. L. Carey, et al. PGC-1alpha gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J.
47. Staron, R. S., R. S. Hikida, F. C. Hagerman, G. A. Dudley, and T. F. Murray. Human skeletal muscle fiber type adaptability to various workloads. J. Histochem. Cytochem.
48. Stitt, T. N., D. Drujan, B. A. Clarke, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell.
49. Streter, F. A., J. Gergely, S. Salmons, and F. Romanul. Synthesis by fast muscle of myosin light chains characteristic of slow muscle in response to long-term stimulation. Nat. New. Biol.
50. Tee, A. R., D. C. Fingar, B. D. Manning, D. J. Kwiatkowski, L. C. Cantley, and J. Blenis. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl. Acad. Sci. U. S. A.
51. Tesch, P. A., and J. Karlsson. Muscle fiber types and size in trained and untrained muscles of elite athletes. J. Appl. Physiol.
52. Thomson, D. M., and S. E. Gordon. Diminished overload-induced hypertrophy in aged fast-twitch skeletal muscle is associated with AMPK hyperphosphorylation. J. Appl. Physiol.
53. Vyas, D. R., E. E. Spangenburg, T. W. Abraha, T. E. Childs, and F. W. Booth. GSK-3beta negatively regulates skeletal myotube hypertrophy. Am. J. Physiol. Cell Physiol.
54. Welsh, G. I., C. M. Miller, A. J. Loughlin, N. T. Price, and C. G. Proud. Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett.
55. 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.
56. Wong, T. S., and F. W. Booth. Skeletal muscle enlargement with weight-lifting exercise by rats. J. Appl. Physiol.
57. Wullschleger, S., R. Loewith, and M. N. Hall. TOR signaling in growth and metabolism. Cell
58. Yan, Z., R. B. Biggs, and F. W. Booth. Insulin-like growth factor immunoreactivity increases in muscle after acute eccentric contractions. J. Appl. Physiol.
This article has been cited 26 time(s).
DiabetesResistance to Aerobic Exercise Training Causes Metabolic Dysfunction and Reveals Novel Exercise-Regulated Signaling NetworksDiabetes
RespirationCardiopulmonary Data in Response to 6 Months of Training in Physically Active Adult Patients with Classic Cystic FibrosisRespiration
Journal of Applied PhysiologyBrief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1 alpha in human skeletal muscleJournal of Applied Physiology
European Journal of Sport ScienceOptimizing training adaptations by manipulating glycogenEuropean Journal of Sport Science
Histology and Histopathology
Intracellular signalling pathways regulating the adaptation of skeletal muscle to exercise and nutritional changes
Histology and Histopathology, 24(2):
European Journal of RadiologyConcentric resistance training increases muscle strength without affecting microcirculationEuropean Journal of Radiology
Journal of Sports SciencesThe specificity of training prescription and physiological assessment: A reviewJournal of Sports Sciences
Applied Physiology Nutrition and Metabolism-Physiologie Appliquee Nutrition Et MetabolismeMolecular responses to high-intensity interval exerciseApplied Physiology Nutrition and Metabolism-Physiologie Appliquee Nutrition Et Metabolisme
Plos OneExercise-Training in Young Drosophila melanogaster Reduces Age-Related Decline in Mobility and Cardiac PerformancePlos One
Biological Research for NursingA Biobehavioral Model for the Study of Exercise Interventions in Cancer-related FatigueBiological Research for Nursing
Scandinavian Journal of Medicine & Science in SportsGeneral introduction to altitude adaptation and mountain sicknessScandinavian Journal of Medicine & Science in Sports
Journal of Applied PhysiologyAMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractionsJournal of Applied Physiology
Agro Food Industry Hi-Tech
Optimising training adaptations by manipulating glycogen
Agro Food Industry Hi-Tech, 19(2):
Strength and Conditioning Journal
Tapering for endurance athletes
Strength and Conditioning Journal, 29(5):
Journal of Physiology-LondonSimilar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humansJournal of Physiology-London
Biological Research for NursingThe biological mechanisms of cancer-related skeletal muscle wasting: The role of progressive resistance exerciseBiological Research for Nursing
Journal of Sports SciencesNutritional strategies to optimize training and racing in middle-distance athletesJournal of Sports Sciences
Experimental GerontologyEffects of high-resistance circuit training in an elderly populationExperimental Gerontology
American Journal of Physiology-Endocrinology and MetabolismResistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscleAmerican Journal of Physiology-Endocrinology and Metabolism
ClinicsA systematic review of the effects of different types of therapeutic exercise on physiologic and functional measurements in patients with HIV/AIDSClinics
Medicine & Science in Sports & ExerciseActive and Passive Tension Interact to Promote Akt Signaling with Muscle ContractionMedicine & Science in Sports & Exercise
Medicine & Science in Sports & ExerciseCycle Training Increased GLUT4 and Activation of Mammalian Target of Rapamycin in Fast Twitch Muscle FibersMedicine & Science in Sports & Exercise
Medicine & Science in Sports & ExerciseGlobal Gene Expression in Skeletal Muscle from Well-Trained Strength and Endurance AthletesMedicine & Science in Sports & Exercise
Medicine & Science in Sports & ExerciseWISE-2005: Exercise and Nutrition Countermeasures for Upright V˙O2pk during Bed RestMedicine & Science in Sports & Exercise
The Journal of Strength & Conditioning ResearchEffects of Two Different Eight-Week Training Programs on Military Physical PerformanceThe Journal of Strength & Conditioning Research
HYPERTROPHY; MITOCHONDRIAL; BIOGENESIS; EXERCISE
©2006The American College of Sports Medicine
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read