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Resistance Exercise Biology

Manipulation of Resistance Exercise Programme Variables Determines the Responses of Cellular and Molecular Signalling Pathways

Abstract

Recent advances in molecular biology have elucidated some of the mechanisms that regulate skeletal muscle growth. Logically, muscle physiologists have applied these innovations to the study of resistance exercise (RE), as RE represents the most potent natural stimulus for growth in adult skeletal muscle. However, as this molecular-based line of research progresses to investigations in humans, scientists must appreciate the fundamental principles of RE to effectively design such experiments. Therefore, we present herein an updated paradigm of RE biology that integrates fundamental RE principles with the current knowledge of muscle cellular and molecular signalling. RE invokes a sequential cascade consisting of: (i) muscle activation; (ii) signalling events arising from mechanical deformation of muscle fibres, hormones, and immune/inflammatory responses; (iii) protein synthesis due to increased transcription and translation; and (iv) muscle fibre hypertrophy. In this paradigm, RE is considered an ‘upstream’ signal that determines specific downstream events. Therefore, manipulation of the acute RE programme variables (i.e. exercise choice, load, volume, rest period lengths, and exercise order) alters the unique ‘fingerprint’ of the RE stimulus and subsequently modifies the downstream cellular and molecular responses.

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Table I

References

  1. Henneman E, Somjen G, Carpenter DO. Functional significance of cell size in spinal motoneurons. J Neurophysiol 1965; 28: 560–80

    PubMed  CAS  Google Scholar 

  2. Linnamo V, Newton RU, Häkkinen K, et al. Neuromuscular responses to explosive and heavy resistance loading. J Electromyogr Kinesiol 2000; 10 (6): 417–24

    PubMed  Article  CAS  Google Scholar 

  3. Pincivero DM, Gandhi V, Timmons MK, et al. Quadriceps femoris electromyogram during concentric, isometric and eccentric phases of fatiguing dynamic knee extensions. J Biomech 2006; 39 (2): 246–54

    PubMed  Article  Google Scholar 

  4. Parkington JD, Siebert AP, Le Brasseur NK, et al. Differential activation of mTOR signaling by contractile activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2003; 285 (5): R1086–90

    Google Scholar 

  5. Mc Call GE, Byrnes WC, Dickinson A, et al. Muscle fiber hypertrophy, hyperplasia, and capillary density in college men after resistance training. J Appl Physiol 1996; 81 (5): 2004–12

    PubMed  CAS  Google Scholar 

  6. Trappe SW, Trappe TA, Lee GA, et al. Comparison of a space shuttle flight (STS−78) and bed rest on human muscle function. J Appl Physiol 2001; 91 (1): 57–64

    PubMed  CAS  Google Scholar 

  7. Hornberger TA, Stuppard R, Conley KE, et al. Mechanical stimuli regulate rapamycin—sensitive signalling by a phosphoinositide 3−kinase—, protein kinase B— and growth factor—independent mechanism. Biochem J 2004; 380 (Pt 3): 795–804

    PubMed  Article  CAS  Google Scholar 

  8. Atherton PJ, Babraj J, Smith K, et al. Selective activation of AMPK—PGC−1alpha or PKB—TSC2−mTOR signaling can explain specific adaptive responses to endurance or resistance training—like electrical muscle stimulation. FASEB J 2005; 19 (7): 786–8

    PubMed  CAS  Google Scholar 

  9. Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001; 3 (11): 1014–9

    PubMed  Article  CAS  Google Scholar 

  10. Hornberger TA, Chu WK, Mak YW, et al. The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proc Natl Acad Sci U S A 2006; 103 (12): 4741–6

    PubMed  Article  CAS  Google Scholar 

  11. Park JB, Kim JH, Kim Y, et al. Cardiac phospholipase D2 localizes to sarcolemmal membranes and is inhibited by alpha—actinin in an ADP—ribosylation factor—reversible manner. J Biol Chem 2000; 275 (28): 21295–301

    PubMed  Article  CAS  Google Scholar 

  12. Terada N, Patel HR, Takase K, et al. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U S A 1994; 91 (24): 11477–81

    PubMed  Article  CAS  Google Scholar 

  13. Kimball SR, Farrell PA, Jefferson LS. Invited review: role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. J Appl Physiol 2002; 93 (3): 1168–80

    PubMed  CAS  Google Scholar 

  14. Sartorelli V, Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE 2004; 2004 (244): re11

    Article  Google Scholar 

  15. Winder WW, Taylor EB, Thomson DM. Role of AMP—activated protein kinase in the molecular adaptation to endurance exercise. Med Sci Sports Exerc 2006; 38 (11): 1945–9

    PubMed  Article  CAS  Google Scholar 

  16. Bolster DR, Crozier SJ, Kimball SR, et al. AMP—activated protein kinase suppresses protein synthesis in rat skeletal muscle through down—regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002; 277 (27): 23977–80

    PubMed  Article  CAS  Google Scholar 

  17. Kimball SR. Interaction between the AMP—activated protein kinase and mTOR signaling pathways. Med Sci Sports Exerc 2006; 38 (11): 1958–64

    PubMed  Article  CAS  Google Scholar 

  18. Dreyer HC, Fujita S, Cadenas JG, et al. Resistance exercise increases AMPK activity and reduces 4E—BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol 2006; 576 (Pt 2): 613–24

    PubMed  Article  CAS  Google Scholar 

  19. Long YC, Widegren U, Zierath JR. Exercise—induced mitogen activated protein kinase signalling in skeletal muscle. Proc Nutr Soc 2004; 63 (2): 227–32

    PubMed  Article  CAS  Google Scholar 

  20. Hawley JA, Zierath JR. Integration of metabolic and mitogenic signal transduction in skeletal muscle. Exerc Sport Sci Rev 2004; 32 (1): 4–8

    PubMed  Article  Google Scholar 

  21. Coffey VG, Zhong Z, Shield A, et al. Early signaling responses to divergent exercise stimuli in skeletal muscle from well trained humans. FASEB J 2006; 20 (1): 190–2

    PubMed  CAS  Google Scholar 

  22. Kraemer WJ, Marchitelli L, Gordon SE, et al. Hormonal and growth factor responses to heavy resistance exercise protocols. J Appl Physiol 1990; 69 (4): 1442–50

    PubMed  CAS  Google Scholar 

  23. Hansen S, Kvorning T, Kjaer M, et al. The effect of short—term strength training on human skeletal muscle: the importance of physiologically elevated hormone levels. Scand J Med Sci Sports 2001; 11 (6): 347–54

    PubMed  Article  CAS  Google Scholar 

  24. Wilkinson SB, Tarnopolsky MA, Grant EJ, et al. Hypertrophy with unilateral resistance exercise occurs without increases in endogenous anabolic hormone concentration. Eur J Appl Physiol 2006; 98 (6): 546–55

    PubMed  Article  CAS  Google Scholar 

  25. Baumann G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr Rev 1991; 12 (4): 424–49

    PubMed  Article  CAS  Google Scholar 

  26. Hymer WC, Kraemer WJ, Nindl BC, et al. Characteristics of circulating growth hormone in women after acute heavy resistance exercise. Am J Physiol Endocrinol Metab 2001; 281 (4): E878–87

    Google Scholar 

  27. Nindl BC, Kraemer WJ, Marx JO, et al. Growth hormone molecular heterogeneity and exercise. Exerc Sport Sci Rev 2003; 31 (4): 161–6

    PubMed  Article  Google Scholar 

  28. Nindl BC. Exercise modulation of growth hormone isoforms: current knowledge and future directions for the exercise endocrinologist. Br J Sports Med 2007; 41 (6): 346–8

    PubMed  Article  CAS  Google Scholar 

  29. Kraemer WJ, Nindl BC, Marx JO, et al. Chronic resistance training in women potentiates growth hormone in vivo bioactivity: characterization of molecular mass variants. Am J Physiol Endocrinol Metab 2006; 291 (6): E1177–87

    Article  Google Scholar 

  30. Piwien-Pilipuk G, Huo JS, Schwartz J. Growth hormone signal transduction. J Pediatr Endocrinol Metab 2002; 15 (6): 771–86

    PubMed  Article  CAS  Google Scholar 

  31. Bush JA, Kimball SR, O’Connor PM, et al. Translational control of protein synthesis in muscle and liver of growth hormone—treated pigs. Endocrinology 2003; 144 (4): 1273–83

    PubMed  Article  CAS  Google Scholar 

  32. Bamman MM, Shipp JR, Jiang J, et al. Mechanical load in creases muscle IGF—I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab 2001; 280 (3): E383–90

    Google Scholar 

  33. Nindl BC, Kraemer WJ, Marx JO, et al. Overnight responses of the circulating IGF—I system after acute, heavy—resistance exercise. J Appl Physiol 2001; 90 (4): 1319–26

    PubMed  CAS  Google Scholar 

  34. Rommel C, Bodine SC, Clarke BA, 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 2001; 3 (11): 1009–13

    PubMed  Article  CAS  Google Scholar 

  35. Frost RA, Lang CH. Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass. J Appl Physiol 2007; 103 (1): 378–87

    PubMed  Article  CAS  Google Scholar 

  36. Hawke TJ. Muscle stem cells and exercise training. Exerc Sport Sci Rev 2005; 33 (2): 63–8

    PubMed  Article  Google Scholar 

  37. Le Roith D, Bondy C, Yakar S, et al. The somatomedin hypothesis: 2001. Endocr Rev 2001; 22 (1): 53–74

    PubMed  Article  Google Scholar 

  38. Kraemer WJ, Aguilera BA, Terada M, et al. Responses of IGF—I to endogenous increases in growth hormone after heavy—resistance exercise. J Appl Physiol 1995; 79 (4): 1310–5

    PubMed  CAS  Google Scholar 

  39. Hameed M, Lange KH, Andersen JL, et al. The effect of recombinant human growth hormone and resistance training on IGF—I mRNA expression in the muscles of elderly men. J Physiol 2004; 555 (Pt 1): 231–40

    PubMed  CAS  Google Scholar 

  40. Kraemer WJ, Häkkinen K, Newton RU, et al. Acute hormonal responses to heavy resistance exercise in younger and older men. Eur J Appl Physiol Occup Physiol 1998; 77 (3): 206–11

    PubMed  Article  CAS  Google Scholar 

  41. Chandler RM, Byrne HK, Patterson JG, et al. Dietary supplements affect the anabolic hormones after weight—training exercise. J Appl Physiol 1994; 76 (2): 839–45

    PubMed  CAS  Google Scholar 

  42. Bloomer RJ, Sforzo GA, Keller BA. Effects of meal form and composition on plasma testosterone, cortisol, and insulin following resistance exercise. Int J Sport Nutr Exerc Metab 2000; 10 (4): 415–24

    PubMed  CAS  Google Scholar 

  43. Kraemer WJ, Gordon SE, Fleck SJ, et al. Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females. Int J Sports Med 1991; 12 (2): 228–35

    PubMed  Article  CAS  Google Scholar 

  44. Inoue K, Yamasaki S, Fushiki T, et al. Androgen receptor antagonist suppresses exercise—induced hypertrophy of skeletal muscle. Eur J Appl Physiol Occup Physiol 1994; 69 (1): 88–91

    PubMed  Article  CAS  Google Scholar 

  45. Sinha-Hikim I, Roth SM, Lee MI, et al. Testosterone—induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab 2003; 285 (1): E197–205

    Google Scholar 

  46. Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004; 7 (3): 271–7

    PubMed  Article  CAS  Google Scholar 

  47. Proske U, Allen TJ. Damage to skeletal muscle from eccentric exercise. Exerc Sport Sci Rev 2005; 33 (2): 98–104

    PubMed  Article  Google Scholar 

  48. Peake J, Nosaka K, Suzuki K. Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev 2005; 11: 64–85

    PubMed  Google Scholar 

  49. Del Aguila LF, Krishnan RK, Ulbrecht JS, et al. Muscle damage impairs insulin stimulation of IRS−1, PI 3−kinase, and Aktkinase in human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 279 (1): E206–12

    Google Scholar 

  50. Kirwan JP, del Aguila LF. Insulin signalling, exercise and cellular integrity. Biochem Soc Trans 2003; 31 (Pt 6): 1281–5

    PubMed  Article  CAS  Google Scholar 

  51. Adams GR, Caiozzo VJ, Haddad F, et al. Cellular and molecular responses to increased skeletal muscle loading after irradiation. Am J Physiol Cell Physiol 2002; 283 (4): C1182–95

    Google Scholar 

  52. Alway SE, Gonyea WJ, Davis ME. Muscle fiber formation and fiber hypertrophy during the onset of stretch—overload. Am J Physiol 1990; 259 (1 Pt 1): C92–102

    Google Scholar 

  53. Kraemer WJ. Exercise prescription in weight training: manipulating program variables. Nat Strength Cond Assoc J 1983; 5: 58–9

    Article  Google Scholar 

  54. Toigo M, Boutellier U. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur J Appl Physiol 2006; 97 (6): 643–63

    PubMed  Article  Google Scholar 

  55. Ballor DL, Becque MD, Katch VL. Metabolic responses during hydraulic resistance exercise. Med Sci Sports Exerc 1987; 19 (4): 363–7

    PubMed  CAS  Google Scholar 

  56. Fahey TD, Rolph R, Moungmee P, et al. Serum testosterone, body composition, and strength of young adults. Med Sci Sports 1976; 8 (1): 31–4

    PubMed  CAS  Google Scholar 

  57. Eliasson J, Elfegoun T, Nilsson J, et al. Maximal lengthening contractions increase p70 S6 kinase phosphorylation in human skeletal muscle in the absence of nutritional supply. Am J Physiol Endocrinol Metab 2006; 291 (6): E1197–205

    Article  Google Scholar 

  58. Garma TM, Kobayashi CA, Haddad F, et al. Similar acute molecular responses to equivalent volumes of isometric, lengthening or shortening mode resistance exercise. J Appl Physiol 2007; 102 (1): 135–43

    PubMed  Article  CAS  Google Scholar 

  59. Baar K, Esser K. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 1999; 276 (1 Pt 1): C120–7

    Google Scholar 

  60. Bolster DR, Kubica N, Crozier SJ, et al. Immediate response of mammalian target of rapamycin (mTOR)—mediated signalling following acute resistance exercise in rat skeletal muscle. J Physiol 2003; 553 (Pt 1): 213–20

    PubMed  Article  CAS  Google Scholar 

  61. Haddad F, Adams GR, Bodell PW, et al. Isometric resistance exercise fails to counteract skeletal muscle atrophy processes during the initial stages of unloading. J Appl Physiol 2006; 100 (2): 433–41

    PubMed  Article  CAS  Google Scholar 

  62. Dudley GA, Tesch PA, Miller BJ, et al. Importance of eccentric actions in performance adaptations to resistance training. Aviat Space Environ Med 1991; 62 (6): 543–50

    PubMed  CAS  Google Scholar 

  63. Sforzo FA, Touey PR. Manipulating exercise order affects muscular performance during a resistance exercise training session. J Strength Cond Res 1996; 10: 20–4

    Google Scholar 

  64. Komi PV, Kaneko M, Aura O. EMG activity of the leg extensor muscles with special reference to mechanical efficiency in concentric and eccentric exercise. Int J Sports Med 1987; 8 Suppl. 1: 22–9

    PubMed  Article  Google Scholar 

  65. Gotshalk LA, Loebel CC, Nindl BC, et al. Hormonal responses of multiset versus single—set heavy—resistance exercise protocols. Can J Appl Physiol 1997; 22 (3): 244–55

    PubMed  Article  CAS  Google Scholar 

  66. Campos GE, Luecke TJ, Wendeln HK, et al. Muscular adaptations in response to three different resistance—training regimens: specificity of repetition maximum training zones. Eur J Appl Physiol 2002; 88 (1-2): 50–60

    PubMed  Article  Google Scholar 

  67. Nader GA, Esser KA. Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. J Appl Physiol 2001; 90 (5): 1936–42

    PubMed  CAS  Google Scholar 

  68. Deschenes MR, Kraemer WJ. Performance and physiologic adaptations to resistance training. Am J Phys Med Rehabil 2002; 81 (11 Suppl.): 3–16

    Article  Google Scholar 

  69. Häkkinen K, Pakarinen A, Alen M, et al. Relationships between training volume, physical performance capacity, and serum hormone concentrations during prolonged training in elite weight lifters. Int J Sports Med 1987; 8 Suppl. 1: 61–5

    PubMed  Article  Google Scholar 

  70. Willoughby DS, Chilek DR, Schiller DA, et al. The metabolic effects of three different free weight parallel squatting intensities. J Hum Mov Stud 1991; 21: 53–67

    Google Scholar 

  71. Berger RA. Effect of varied weight training programs on strength. Res Q 1962; 33: 168–81

    Google Scholar 

  72. Borst SE, De Hoyos DV, Garzarella L, et al. Effects of resistance training on insulin—like growth factor—I and IGF binding proteins. Med Sci Sports Exerc 2001; 33 (4): 648–53

    PubMed  CAS  Google Scholar 

  73. Sanborn K, Boros R, Hruby J, et al. Short—term performance effects of weight training with multiple sets not to failure vs a single set to failure in women. J Strength Cond Res 2000; 14: 328–31

    Google Scholar 

  74. Stowers T, Mc Millian J, Scala D, et al. The short—term effects of three different strength—power training models. NSCA J 1983; 5: 24–7

    Google Scholar 

  75. Steinberg GR, Watt MJ, Mc Gee SL, et al. Reduced glycogen availability is associated with increased AMPKa2 activity, nuclear AMPKa2 protein abundance, and GLUT4 mRNA expression in contracting human skeletal muscle. Appl Physiol Nutr Metab 2006; 31 (3): 302–12

    PubMed  Article  CAS  Google Scholar 

  76. Churchley EG, Coffey VG, Pedersen DJ, et al. Influence of preexercise muscle glycogen content on transcriptional activity of metabolic and myogenic genes in well—trained humans. J Appl Physiol 2007; 102 (4): 1604–11

    PubMed  Article  CAS  Google Scholar 

  77. Creer A, Gallagher P, Slivka D, et al. Influence of muscle glycogen availability on ERK1/2 and Akt signaling after resistance exercise in human skeletal muscle. J Appl Physiol 2005; 99 (3): 950–6

    PubMed  Article  CAS  Google Scholar 

  78. Wong TS, Booth FW. Protein metabolism in rat tibialis anterior muscle after stimulated chronic eccentric exercise. J Appl Physiol 1990; 69 (5): 1718–24

    PubMed  CAS  Google Scholar 

  79. Wong TS, Booth FW. Protein metabolism in rat gastrocnemius muscle after stimulated chronic concentric exercise. J Appl Physiol 1990; 69 (5): 1709–17

    PubMed  CAS  Google Scholar 

  80. Wong TS, Booth FW. Skeletal muscle enlargement with weightlifting exercise by rats. J Appl Physiol 1988; 65 (2): 950–4

    PubMed  CAS  Google Scholar 

  81. Kraemer WJ, Fleck SJ, Dziados JE, et al. Changes in hormonal concentrations after different heavy—resistance exercise protocols in women. J Appl Physiol 1993; 75 (2): 594–604

    PubMed  CAS  Google Scholar 

  82. Robinson JM, Stone MH, Johnson RL, et al. Effects of different weight training exercise/rest intervals on strength, power, and high intensity exercise endurance. J Strength Cond Res 1995; 9: 216–21

    Google Scholar 

  83. Kraemer WJ, Adams K, Cafarelli E, et al. American College of Sports Medicine position stand: progression models in resistance training for healthy adults. Med Sci Sports Exerc 2002; 34 (2): 364–80

    PubMed  Article  Google Scholar 

  84. Kraemer WJ, Noble BJ, Clark MJ, et al. Physiologic responses to heavy—resistance exercise with very short rest periods. Int J Sports Med 1987; 8 (4): 247–52

    PubMed  Article  CAS  Google Scholar 

  85. Spreuwenberg LP, Kraemer WJ, Spiering BA, et al. Influence of exercise order in a resistance—training exercise session. J Strength Cond Res 2006; 20 (1): 141–4

    PubMed  Google Scholar 

  86. Häkkinen K, Komi PV, Alen M. Effect of explosive type strength training on isometric force— and relaxation—time, electromyographic and muscle fibre characteristics of leg extensor muscles. Acta Physiol Scand 1985; 125 (4): 587–600

    PubMed  Article  Google Scholar 

  87. Augustsson J, Thomee R, Hornstedt P, et al. Effect of preexhaustion exercise on lower—extremity muscle activation during a leg press exercise. J Strength Cond Res 2003; 17 (2): 411–6

    PubMed  Google Scholar 

  88. Rasmussen BB, Phillips SM. Contractile and nutritional regulation of human muscle growth. Exerc Sport Sci Rev 2003; 31 (3): 127–31

    PubMed  Article  Google Scholar 

  89. Wolfe RR. Effects of amino acid intake on anabolic processes. Can J Appl Physiol 2001; 26 Suppl.: 220–7

    Article  Google Scholar 

  90. Rennie MJ, Bohe J, Smith K, et al. Branched—chain amino acids as fuels and anabolic signals in human muscle. J Nutr 2006; 136 (1 Suppl.): 264S–8

    PubMed  CAS  Google Scholar 

  91. Blomstrand E, Eliasson J, Karlsson HK, et al. Branched—chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr 2006; 136 (1 Suppl.): 269S–73

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported, in part, by graduate student research grants awarded by the National Strength and Conditioning Association and the University of Connecticut. The authors would like to thank Dr Daniel A. Judelson for critically reading the manuscript and providing thoughtful comments, and Dr P. Courtney Gaine for her insightful discussions. The authors have no conflicts of interest directly relevant to the contents of this article.

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Spiering, B.A., Kraemer, W.J., Anderson, J.M. et al. Resistance Exercise Biology. Sports Med 38, 527–540 (2008). https://doi.org/10.2165/00007256-200838070-00001

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Keywords

  • Satellite Cell
  • Resistance Exercise
  • Muscle Growth
  • Exercise Load
  • Satellite Cell Activity