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Sports Medicine

, Volume 46, Issue 5, pp 671–685 | Cite as

Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise: Implications for Muscle Hypertrophy

  • Adam M. Gonzalez
  • Jay R. Hoffman
  • Jeffrey R. Stout
  • David H. Fukuda
  • Darryn S. Willoughby
Review Article

Abstract

Maintaining skeletal muscle mass and function is critical for disease prevention, mobility and quality of life, and whole-body metabolism. Resistance exercise is known to be a major regulator for promoting muscle protein synthesis and muscle mass accretion. Manipulation of exercise intensity, volume, and rest elicit specific muscular adaptations that can maximize the magnitude of muscle growth. The stimulus of muscle contraction that occurs during differing intensities of resistance exercise results in varying biochemical responses regulating the rate of protein synthesis, known as mechanotransduction. At the cellular level, skeletal muscle adaptation appears to be the result of the cumulative effects of transient changes in gene expression following acute bouts of exercise. Thus, maximizing the resistance exercise-induced anabolic response produces the greatest potential for hypertrophic adaptation with training. The mechanisms involved in converting mechanical signals into the molecular events that control muscle growth are not completely understood; however, skeletal muscle protein synthesis appears to be regulated by the multi-protein phosphorylation cascade, mTORC1 (mammalian/mechanistic target of rapamycin complex 1). The purpose of this review is to examine the physiological response to resistance exercise, with particular emphasis on the endocrine response and intramuscular anabolic signaling through mTORC1. It appears that resistance exercise protocols that maximize muscle fiber recruitment, time-under-tension, and metabolic stress will contribute to maximizing intramuscular anabolic signaling; however, the resistance exercise parameters for maximizing the anabolic response remain unclear.

Keywords

Resistance Training Resistance Exercise Phosphatidic Acid Muscle Hypertrophy Muscle Protein Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Funding

No sources of funding were used to assist in the preparation of this article.

Conflict of interest

Adam Gonzalez, Jay Hoffman, Jeffrey Stout, David Fukuda, and Darryn Willoughby declare that they have no conflicts of interest relevant to the content of this review.

References

  1. 1.
    Braith RW, Stewart KJ. Resistance exercise training its role in the prevention of cardiovascular disease. Circulation. 2006;113(22):2642–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Yanagita M, Shiotsu Y. Role of resistance training for preventing frailty and metabolic syndromes in aged adults. J Phys Fit Sports Med. 2014;3(1):35–42.CrossRefGoogle Scholar
  3. 3.
    Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50(5):889–96.PubMedCrossRefGoogle Scholar
  4. 4.
    Peterson MD, Gordon PM. Resistance exercise for the aging adult: clinical implications and prescription guidelines. Am J Med. 2011;124(3):194–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Baskin KK, Winders BR, Olson EN. Muscle as a “mediator” of systemic metabolism. Cell Metab. 2015;21(2):237–48.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Goodman CA, Mayhew DL, Hornberger TA. Recent progress toward understanding the molecular mechanisms that regulate skeletal muscle mass. Cell Signal. 2011;23(12):1896–906.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Greenhaff PL, Karagounis L, Peirce N, et al. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab. 2008;295(3):E595–604.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Lüthi J, Howald H, Claassen H, et al. Structural changes in skeletal muscle tissue with heavy-resistance exercise. Int J Sports Med. 1986;7(3):123–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Paul AC, Rosenthal N. Different modes of hypertrophy in skeletal muscle fibers. J Cell Biol. 2002;156(4):751–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Toigo M, Boutellier U. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur J Appl Physiol. 2006;97(6):643–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Kelley G. Mechanical overload and skeletal muscle fiber hyperplasia: a meta-analysis. J Appl Physiol. 1996;81(4):1584–8.PubMedGoogle Scholar
  12. 12.
    Phillips SM, Tipton KD, Aarsland A, et al. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol Endocrinol Metab. 1997;36(1):E99.Google Scholar
  13. 13.
    Yarasheski KE, Zachwieja JJ, Bier DM. Acute effects of resistance exercise on muscle protein synthesis rate in young and elderly men and women. Am J Physiol. 1993;265:E210-E.Google Scholar
  14. 14.
    MacDougall JD, Gibala MJ, Tarnopolsky MA, et al. The time course for elevated muscle protein synthesis following heavy resistance exercise. Can J Appl Physiol. 1995;20(4):480–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Chesley A, MacDougall J, Tarnopolsky M, et al. Changes in human muscle protein synthesis after resistance exercise. J Appl Physiol. 1992;73:1383–8.PubMedGoogle Scholar
  16. 16.
    Aagaard P, Andersen JL, Dyhre-Poulsen P, et al. A mechanism for increased contractile strength of human pennate muscle in response to strength training: changes in muscle architecture. J Physiol. 2001;534(2):613–23.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bell G, Syrotuik D, Martin T, et al. Effect of concurrent strength and endurance training on skeletal muscle properties and hormone concentrations in humans. Eur J Appl Physiol. 2000;81(5):418–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Seynnes OR, de Boer M, Narici MV. Early skeletal muscle hypertrophy and architectural changes in response to high-intensity resistance training. J Appl Physiol. 2007;102(1):368–73.PubMedCrossRefGoogle Scholar
  19. 19.
    McCall G, Byrnes W, 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.PubMedGoogle Scholar
  20. 20.
    Adams GR, Bamman MM. Characterization and regulation of mechanical loading-induced compensatory muscle hypertrophy. Compr Physiol. 2012;2(4):2829–70.PubMedGoogle Scholar
  21. 21.
    Hornberger TA. Mechanotransduction and the regulation of mTORC1 signaling in skeletal muscle. Int J Biochem Cell Biol. 2011;43(9):1267–76.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Coffey VG, Hawley JA. The molecular bases of training adaptation. Sports Med. 2007;37(9):737–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Tanimoto M, Ishii N. Effects of low-intensity resistance exercise with slow movement and tonic force generation on muscular function in young men. J Appl Physiol. 2006;100(4):1150–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Mitchell CJ, Churchward-Venne TA, West DW, et al. Resistance exercise load does not determine training-mediated hypertrophic gains in young men. J Appl Physiol. 2012;113(1):71–7.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ogasawara R, Loenneke JP, Thiebaud RS, et al. Low-load bench press training to fatigue results in muscle hypertrophy similar to high-load bench press training. Int J Clin Med. 2013;4(2):114.CrossRefGoogle Scholar
  26. 26.
    Kraemer WJ, Nindl BC, Ratamess NA, et al. Changes in muscle hypertrophy in women with periodized resistance training. Med Sci Sports Exerc. 2004;36(4):697–708.PubMedCrossRefGoogle Scholar
  27. 27.
    Popov D, Swirkun D, Netreba A, et al. Hormonal adaptation determines the increase in muscle mass and strength during low-intensity strength training without relaxation. Hum Physiol. 2006;32(5):609–14.CrossRefGoogle Scholar
  28. 28.
    Hisaeda H, Miyagawa K, Kuno S, et al. Influence of two different modes of resistance training in female subjects. Ergonomics. 1996;39(6):842.PubMedCrossRefGoogle Scholar
  29. 29.
    Chestnut JL, Docherty D. The effects of 4 and 10 repetition maximum weight-training protocols on neuromuscular adaptations in untrained men. J Strength Cond Res. 1999;13(4):353–9.Google Scholar
  30. 30.
    Léger B, Cartoni R, Praz M, et al. Akt signalling through GSK-3β, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. J Physiol. 2006;576(3):923–33.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lamon S, Wallace MA, Léger B, et al. Regulation of stars and its downstream targets suggest a novel pathway involved in human skeletal muscle hypertrophy and atrophy. J Physiol. 2009;587(8):1795–803.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Alegre LM, Aguado X, Rojas-Martín D, et al. Load-controlled moderate and high-intensity resistance training programs provoke similar strength gains in young women. Muscle Nerve. 2015;51(1):92–101.PubMedCrossRefGoogle Scholar
  33. 33.
    Tanimoto M, Sanada K, Yamamoto K, et al. Effects of whole-body low-intensity resistance training with slow movement and tonic force generation on muscular size and strength in young men. J Strength Cond Res. 2008;22(6):1926–38.PubMedCrossRefGoogle Scholar
  34. 34.
    Holm L, Reitelseder S, Pedersen TG, et al. Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity. J Appl Physiol. 2008;105(5):1454–61.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Schuenke MD, Herman JR, Gliders RM, et al. Early-phase muscular adaptations in response to slow-speed versus traditional resistance-training regimens. Eur J Appl Physiol. 2012;112(10):3585–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Masuda K, Choi JY, Shimojo H, et al. Maintenance of myoglobin concentration in human skeletal muscle after heavy resistance training. Eur J Appl Physiol Occup Physiol. 1999;79(4):347–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Choi J, Takahashi H, Itai Y, et al. The difference between effects of “power-up type” and “bulk-up type” strength training exercises-with special reference to muscle cross-sectional area, muscular strength, anaerobic power and anaerobic endurance. Jpn J Phys Fit Sports Med. 1998;47(1):119–29.Google Scholar
  39. 39.
    Krieger JW. Single vs. multiple sets of resistance exercise for muscle hypertrophy: a meta-analysis. J Strength Cond Res. 2010;24(4):1150–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Kim PL, Staron RS, Phillips SM. Fasted-state skeletal muscle protein synthesis after resistance exercise is altered with training. J Physiol. 2005;568(1):283–90.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Phillips SM, Tipton K, Ferrando AA, et al. Resistance training reduces the acute exercise-induced increase in muscle protein turnover. Am J Physiol Endocrinol Metab. 1999;276(1):E118–24.Google Scholar
  42. 42.
    Tang JE, Perco JG, Moore DR, et al. Resistance training alters the response of fed state mixed muscle protein synthesis in young men. Am J Phys Reg Integr Compar Physiol. 2008;294(1):R172–8.CrossRefGoogle Scholar
  43. 43.
    Coffey V, 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.PubMedGoogle Scholar
  44. 44.
    Nader GA, von Walden F, Liu C, et al. Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy. J Appl Physiol. 2014;116(6):693–702.PubMedCrossRefGoogle Scholar
  45. 45.
    Gonzalez AM, Hoffman JR, Townsend JR, et al. Association between myosin heavy chain protein isoforms and intramuscular anabolic signaling following resistance exercise in trained men. Physiol Rep. 2015;3(1):e12268.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Schoenfeld BJ, Ratamess NA, Peterson MD, et al. Effects of different volume-equated resistance training loading strategies on muscular adaptations in well-trained men. J Strength Cond Res. 2014;28(10):2909–18.PubMedCrossRefGoogle Scholar
  47. 47.
    Schoenfeld BJ, Peterson MD, Ogborn D, et al. Effects of low-versus high-load resistance training on muscle strength and hypertrophy in well-trained men. J Strength Cond Res. 2015;29(10):2954–63.PubMedCrossRefGoogle Scholar
  48. 48.
    Gehlert S, Suhr F, Gutsche K, et al. High force development augments skeletal muscle signalling in resistance exercise modes equalized for time under tension. Pflügers Arch. 2014;467(6):1343–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Burd NA, Andrews RJ, West DW, et al. Muscle time under tension during resistance exercise stimulates differential muscle protein sub-fractional synthetic responses in men. J Physiol. 2012;590(2):351–62.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Popov DV, Lysenko EA, Bachinin AV, et al. Influence of resistance exercise intensity and metabolic stress on anabolic signaling and expression of myogenic genes in skeletal muscle. Muscle Nerve. 2015;51(3):434–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Timmons JA. Variability in training-induced skeletal muscle adaptation. J Appl Physiol. 2011;110(3):846–53.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Bamman MM, Petrella JK, Kim J, et al. Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans. J Appl Physiol. 2007;102(6):2232–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Hubal MJ, Gordish-Dressman H, Thompson PD, et al. Variability in muscle size and strength gain after unilateral resistance training. Med Sci Sports Exerc. 2005;37(6):964–72.PubMedGoogle Scholar
  54. 54.
    Mitchell CJ, Churchward-Venne TA, Bellamy L, et al. Muscular and systemic correlates of resistance training-induced muscle hypertrophy. PLoS One. 2013;8(10):e78636.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Koopman R, Zorenc AH, Gransier RJ, et al. Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers. Am J Physiol Endocrinol Metab. 2006;290(6):E1245–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Schoenfeld BJ, Ratamess NA, Peterson MD, et al. Influence of resistance training frequency on muscular adaptations in well-trained men. J Strength Cond Res. 2015;29(7):1821–9.PubMedCrossRefGoogle Scholar
  57. 57.
    McDonagh M, Davies C. Adaptive response of mammalian skeletal muscle to exercise with high loads. Eur J Appl Physiol Occup Physiol. 1984;52(2):139–55.PubMedCrossRefGoogle Scholar
  58. 58.
    Wernbom M, Augustsson J, Thomeé R. The influence of frequency, intensity, volume and mode of strength training on whole muscle cross-sectional area in humans. Sports Med. 2007;37(3):225–64.PubMedCrossRefGoogle Scholar
  59. 59.
    Fry AC. The role of resistance exercise intensity on muscle fibre adaptations. Sports Med. 2004;34(10):663–79.PubMedCrossRefGoogle Scholar
  60. 60.
    Burd NA, West DW, Staples AW, et al. Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PLoS One. 2010;5(8):e12033.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Crewther B, Cronin J, Keogh J, et al. The salivary testosterone and cortisol response to three loading schemes. J Strength Cond Res. 2008;22(1):250–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Hakkinen K, Pakarinen A. Acute hormonal responses to two different fatiguing heavy-resistance protocols in male athletes. J Appl Physiol. 1993;74(2):882–7.PubMedGoogle Scholar
  63. 63.
    Linnamo V, Pakarinen A, Komi PV, et al. Acute hormonal responses to submaximal and maximal heavy resistance and explosive exercises in men and women. J Strength Cond Res. 2005;19(3):566–71.PubMedGoogle Scholar
  64. 64.
    McCaulley GO, McBride JM, Cormie P, et al. Acute hormonal and neuromuscular responses to hypertrophy, strength and power type resistance exercise. Eur J Appl Physiol. 2009;105(5):695–704.PubMedCrossRefGoogle Scholar
  65. 65.
    Smilios I, Pilianidis T, Karamouzis M, et al. Hormonal responses after various resistance exercise protocols. Med Sci Sports Exerc. 2003;35(4):644–54.PubMedCrossRefGoogle Scholar
  66. 66.
    Uchida MC, Crewther BT, Ugrinowitsch C, et al. Hormonal responses to different resistance exercise schemes of similar total volume. J Strength Cond Res. 2009;23(7):2003–8.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedGoogle Scholar
  68. 68.
    West DW, Burd NA, Tang JE, et al. Elevations in ostensibly anabolic hormones with resistance exercise enhance neither training-induced muscle hypertrophy nor strength of the elbow flexors. J Appl Physiol. 2010;108(1):60–7.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    West DW, Burd NA, Staples AW, et al. Human exercise-mediated skeletal muscle hypertrophy is an intrinsic process. Int J Biochem Cell Biol. 2010;42(9):1371–5.PubMedCrossRefGoogle Scholar
  70. 70.
    West DW, Kujbida GW, Moore DR, et al. Resistance exercise-induced increases in putative anabolic hormones do not enhance muscle protein synthesis or intracellular signalling in young men. J Physiol. 2009;587(21):5239–47.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Goldberg AL, Etlinger JD, Goldspink DF, et al. Mechanism of work-induced hypertrophy of skeletal muscle. Med Sci Sports. 1974;7(3):185–98.Google Scholar
  72. 72.
    Brian M, Bilgen E, Diane CF. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 2012;441(1):1–21.CrossRefGoogle Scholar
  73. 73.
    Drummond MJ, Fry CS, Glynn EL, et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol. 2009;587(7):1535–46.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Hornberger TA, Sukhija KB, Chien S. Regulation of mTOR by mechanically induced signaling events in skeletal muscle. Cell Cycle. 2006;5(13):1391–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Goodman CA. The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli. Rev Physiol Biochem Pharmacol. 2014;166:43–95.PubMedGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Anthony JC, Yoshizawa F, Anthony TG, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000;130(10):2413–9.PubMedGoogle Scholar
  79. 79.
    Kubica N, Bolster DR, Farrell PA, et al. Resistance exercise increases muscle protein synthesis and translation of eukaryotic initiation factor 2bϵ mRNA in a mammalian target of rapamycin-dependent manner. J Biol Chem. 2005;280(9):7570–80.PubMedCrossRefGoogle Scholar
  80. 80.
    Gundermann DM, Walker DK, Reidy PT, et al. Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin. Am J Physiol Endocrinol Metab. 2014;306(10):E1198–204.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hornberger TA, McLoughlin TJ, Leszczynski JK, et al. Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth. J Nutr. 2003;133(10):3091–7.PubMedGoogle Scholar
  82. 82.
    Kumar V, Selby A, Rankin D, et al. Age-related differences in the dose–response relationship of muscle protein synthesis to resistance exercise in young and old men. J Physiol. 2009;587(1):211–7.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Burd NA, Holwerda AM, Selby KC, et al. Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men. J Physiol. 2010;588(16):3119–30.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Baar K, Esser K. Phosphorylation of p70s6k correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol Cell Physiol. 1999;276(1):C120–7.Google Scholar
  85. 85.
    Terzis G, Georgiadis G, Stratakos G, et al. Resistance exercise-induced increase in muscle mass correlates with p70s6 kinase phosphorylation in human subjects. Eur J Appl Physiol. 2008;102(2):145–52.PubMedCrossRefGoogle Scholar
  86. 86.
    Mayhew DL, J-s Kim, Cross JM, et al. Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans. J Appl Physiol. 2009;107(5):1655–62.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Goodman CA, Frey JW, Mabrey DM, et al. The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. J Physiol. 2011;589(22):5485–501.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Marcotte GR, West DW, Baar K. The molecular basis for load-induced skeletal muscle hypertrophy. Calc Tiss Int. 2014;96(3):196–210.CrossRefGoogle Scholar
  89. 89.
    Sato T, Nakashima A, Guo L, et al. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284(19):12783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Tee AR, Manning BD, Roux PP, et al. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003;13(15):1259–68.PubMedCrossRefGoogle Scholar
  91. 91.
    Menon S, Dibble CC, Talbott G, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156(4):771–85.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology. 2008;23(3):160–70.PubMedCrossRefGoogle Scholar
  93. 93.
    Jacobs BL, You J-S, Frey JW, et al. Eccentric contractions increase the phosphorylation of tuberous sclerosis complex-2 (TSC2) and alter the targeting of TSC2 and the mechanistic target of rapamycin to the lysosome. J Physiol. 2013;591(18):4611–20.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Hornberger T, Stuppard R, Conley K, et al. Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism. Biochem J. 2004;380:795–804.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Deldicque L, Atherton P, Patel R, et al. Effects of resistance exercise with and without creatine supplementation on gene expression and cell signaling in human skeletal muscle. J Appl Physiol. 2008;104(2):371–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Deldicque L, Atherton P, Patel R, et al. Decrease in Akt/PKB signalling in human skeletal muscle by resistance exercise. Eur J Appl Physiol. 2008;104(1):57–65.PubMedCrossRefGoogle Scholar
  97. 97.
    Hornberger T, Chu W, Mak Y, et al. The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proc Natl Acad Sci. 2006;103(12):4741–6.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    You J-S, Lincoln HC, Kim C-R, et al. The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem. 2014;289(3):1551–63.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Tang W, Yuan J, Chen X, et al. Identification of a novel human lysophosphatidic acid acyltransferase, LPAAT-theta, which activates mTOR pathway. J Biochem Mol Biol. 2006;39(5):626.PubMedCrossRefGoogle Scholar
  100. 100.
    Ávila-Flores A, Santos T, Rincón E, et al. Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J Biol Chem. 2005;280(11):10091–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Fang Y, Vilella-Bach M, Bachmann R, et al. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001;294(5548):1942–5.PubMedCrossRefGoogle Scholar
  102. 102.
    Chen J, Fang Y. A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem Pharmacol. 2002;64(7):1071–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Sun Y, Fang Y, Yoon M-S, et al. Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc Natl Acad Sci. 2008;105(24):8286–91.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Wang X, Devaiah SP, Zhang W, et al. Signaling functions of phosphatidic acid. Progr Lipid Res. 2006;45(3):250–78.CrossRefGoogle Scholar
  105. 105.
    Foster DA, Salloum D, Menon D, et al. Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR). J Biol Chem. 2014;289(33):22583–8.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Joy JM, Gundermann DM, Lowery RP, et al. Phosphatidic acid enhances mTOR signaling and resistance exercise induced hypertrophy. Nutr Metab. 2014;11(1):29.CrossRefGoogle Scholar
  107. 107.
    Shepherd P, Withers D, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. 1998;333:471–90.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Alessi DR, Cohen P. Mechanism of activation and function of protein kinase B. Curr Opin Gen Dev. 1998;8(1):55–62.CrossRefGoogle Scholar
  109. 109.
    Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B. Curr Biol. 1997;7(4):261–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–57.PubMedCrossRefGoogle Scholar
  111. 111.
    Vander Haar E, Lee S-I, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate pras40. Nat Cell Biol. 2007;9(3):316–23.Google Scholar
  112. 112.
    Veldhuis JD, Roemmich JN, Richmond EJ, et al. Endocrine control of body composition in infancy, childhood, and puberty. Endocr Rev. 2005;26(1):114–46.PubMedCrossRefGoogle Scholar
  113. 113.
    Solomon A, Bouloux P. Modifying muscle mass–the endocrine perspective. J Endocrinol. 2006;191(2):349–60.PubMedCrossRefGoogle Scholar
  114. 114.
    Schroeder ET, Villanueva M, West D, et al. Are acute post-resistance exercise increases in testosterone, growth hormone, and IGF-1 necessary to stimulate skeletal muscle anabolism and hypertrophy? Med Sci Sports Exerc. 2013;45(11):2044–51.PubMedCrossRefGoogle Scholar
  115. 115.
    McCall GE, Byrnes WC, Fleck SJ, et al. Acute and chronic hormonal responses to resistance training designed to promote muscle hypertrophy. Can J Appl Physiol. 1999;24(1):96–107.PubMedCrossRefGoogle Scholar
  116. 116.
    Ahtiainen JP, Pakarinen A, Alen M, et al. Muscle hypertrophy, hormonal adaptations and strength development during strength training in strength-trained and untrained men. Eur J Appl Physiol. 2003;89(6):555–63.PubMedCrossRefGoogle Scholar
  117. 117.
    Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med. 2005;35(4):339–61.PubMedCrossRefGoogle Scholar
  118. 118.
    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.PubMedCrossRefGoogle Scholar
  119. 119.
    Spiering BA, Kraemer WJ, Anderson JM, et al. Effects of elevated circulating hormones on resistance exercise-induced Akt signaling. Med Sci Sports Exerc. 2008;40(6):1039–48.PubMedCrossRefGoogle Scholar
  120. 120.
    Griggs RC, Kingston W, Jozefowicz RF, et al. Effect of testosterone on muscle mass and muscle protein synthesis. J Appl Physiol. 1989;66(1):498–503.PubMedGoogle Scholar
  121. 121.
    Ferrando AA, Tipton KD, Doyle D, et al. Testosterone injection stimulates net protein synthesis but not tissue amino acid transport. Am J Physiol Endocrinol Metab. 1998;275(5):E864–71.Google Scholar
  122. 122.
    Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335(1):1–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172–81.PubMedGoogle Scholar
  124. 124.
    Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992;75(4):1092–8.PubMedGoogle Scholar
  125. 125.
    Tenover JL. Experience with testosterone replacement in the elderly. Mayo Clin Proc. 2000;75(Suppl): S77–81 (discussion S82).Google Scholar
  126. 126.
    Morley JE, Perry H, Kaiser F, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 1993;41(2):149–52.PubMedCrossRefGoogle Scholar
  127. 127.
    Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82(6):1661–7.PubMedCrossRefGoogle Scholar
  128. 128.
    Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84(8):2647–53.PubMedGoogle Scholar
  129. 129.
    Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: Molecular and physiological mechanisms. Am J Physiol Endocrinol Metab. 2002;282(3):E601–7.PubMedCrossRefGoogle Scholar
  130. 130.
    McGlory C, Phillips SM. Exercise and the regulation of skeletal muscle hypertrophy. Progr Mol Biol Trans Sci. 2015;135:153–73.CrossRefGoogle Scholar
  131. 131.
    Goodman CA, Miu MH, Frey JW, et al. A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy. Mol Biol Cell. 2010;21(18):3258–68.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ahtiainen JP, Pakarinen A, Alen M, et al. Short vs. long rest period between the sets in hypertrophic resistance training: Influence on muscle strength, size, and hormonal adaptations in trained men. J Strength Cond Res. 2005;19(3):572–82.PubMedGoogle Scholar
  133. 133.
    Boroujerdi SS, Rahimi R. Acute GH and IGF-I responses to short vs. long rest period between sets during forced repetitions resistance training system. S Afr J Res Sport Phys Educ Recreat. 2008;30(2):31–8.Google Scholar
  134. 134.
    Beaven CM, Gill ND, Cook CJ. Salivary testosterone and cortisol responses in professional rugby players after four resistance exercise protocols. J Strength Cond Res. 2008;22(2):426–32.PubMedCrossRefGoogle Scholar
  135. 135.
    Goto K, Sato K, Takamatsu K. A single set of low intensity resistance exercise immediately following high intensity resistance exercise stimulates growth hormone secretion in men. J Phys Fit Sports Med. 2003;43(2):243–9.Google Scholar
  136. 136.
    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.PubMedGoogle Scholar
  137. 137.
    Kraemer WJ, Häkkinen K, Newton RU, et al. Effects of heavy-resistance training on hormonal response patterns in younger vs. older men. J Appl Physiol. 1999;87(3):982–92.PubMedGoogle Scholar
  138. 138.
    Villanueva MG, Villanueva MG, Lane CJ, et al. Influence of rest interval length on acute testosterone and cortisol responses to volume-load–equated total body hypertrophic and strength protocols. J Strength Cond Res. 2012;26(10):2755–64.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Raastad T, Bjøro T, Hallen J. Hormonal responses to high-and moderate-intensity strength exercise. Eur J Appl Physiol. 2000;82(1–2):121–8.PubMedCrossRefGoogle Scholar
  140. 140.
    West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2012;112(7):2693–702.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Mitchell CJ, Churchward-Venne TA, Parise G, et al. Acute post-exercise myofibrillar protein synthesis is not correlated with resistance training-induced muscle hypertrophy in young men. PLoS One. 2014;9(2):e89431.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Sheffield-Moore M. Androgens and the control of skeletal muscle protein synthesis. Ann Med. 2000;32(3):181–6.PubMedCrossRefGoogle Scholar
  143. 143.
    Willoughby DS, Taylor L. Effects of sequential bouts of resistance exercise on androgen receptor expression. Med Sci Sports Exerc. 2004;36(9):1499–506.PubMedCrossRefGoogle Scholar
  144. 144.
    Bricout V, Germain P, Serrurier B, et al. Changes in testosterone muscle receptors: effects of an androgen treatment on physically trained rats. Cell Mol Biol. 1994;40(3):291–4.PubMedGoogle Scholar
  145. 145.
    Lu Y, Tong Q, He L. The effect of exercise on the androgen receptor binding capacity and the level of testosterone in the skeletal muscle. Chin J Appl Physiol. 1997;13(3):198–201.Google Scholar
  146. 146.
    Bamman MM, Shipp JR, Jiang J, et al. Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab. 2001;280(3):E383–90.PubMedGoogle Scholar
  147. 147.
    Deschenes MR, Maresh CM, Armstrong LE, et al. Endurance and resistance exercise induce muscle fiber type specific responses in androgen binding capacity. J Steroid Biochem Mol Biol. 1994;50(3):175–9.PubMedCrossRefGoogle Scholar
  148. 148.
    Kadi F, Bonnerud P, Eriksson A, et al. The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids. Histochem Cell Biol. 2000;113(1):25–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Ratamess NA, Kraemer WJ, Volek JS, et al. Androgen receptor content following heavy resistance exercise in men. J Steroid Biochem Mol Biol. 2005;93(1):35–42.PubMedCrossRefGoogle Scholar
  150. 150.
    Vingren JL, Kraemer WJ, Hatfield DL, et al. Effect of resistance exercise on muscle steroid receptor protein content in strength-trained men and women. Steroids. 2009;74(13):1033–9.PubMedCrossRefGoogle Scholar
  151. 151.
    Vingren JL, Kraemer WJ, Ratamess NA, et al. Testosterone physiology in resistance exercise and training. Sports Med. 2010;40(12):1037–53.PubMedCrossRefGoogle Scholar
  152. 152.
    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.PubMedCrossRefGoogle Scholar
  153. 153.
    Kvorning T, Andersen M, Brixen K, et al. Suppression of testosterone does not blunt mRNA expression of myoD, myogenin, IGF, myostatin or androgen receptor post strength training in humans. J Physiol. 2007;578(2):579–93.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Spangenburg EE, Le Roith D, Ward CW, et al. A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. J Physiol. 2008;586(1):283–91.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Rønnestad BR, Nygaard H, Raastad T. Physiological elevation of endogenous hormones results in superior strength training adaptation. Eur J Appl Physiol. 2011;111(9):2249–59.PubMedCrossRefGoogle Scholar
  156. 156.
    West DW, Cotie LM, Mitchell CJ, et al. Resistance exercise order does not determine postexercise delivery of testosterone, growth hormone, and IGF-1 to skeletal muscle. Appl Physiol Nutr Metab. 2012;38(2):220–6.PubMedCrossRefGoogle Scholar
  157. 157.
    Apró W, Blomstrand E. Influence of supplementation with branched-chain amino acids in combination with resistance exercise on p70s6 kinase phosphorylation in resting and exercising human skeletal muscle. Acta Physiol. 2010;200(3):237–48.CrossRefGoogle Scholar
  158. 158.
    Deldicque L, De Bock K, Maris M, et al. Increased p70s6k phosphorylation during intake of a protein–carbohydrate drink following resistance exercise in the fasted state. Eur J Appl Physiol. 2010;108(4):791–800.PubMedCrossRefGoogle Scholar
  159. 159.
    Farnfield MM, Carey KA, Gran P, et al. Whey protein ingestion activates mTOR-dependent signalling after resistance exercise in young men: a double-blinded randomized controlled trial. Nutrients. 2009;1(2):263–75.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Hulmi JJ, Tannerstedt J, Selänne H, et al. Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men. J Appl Physiol. 2009;106(5):1720–9.PubMedCrossRefGoogle Scholar
  161. 161.
    Karlsson HK, Nilsson P-A, Nilsson J, et al. Branched-chain amino acids increase p70s6k phosphorylation in human skeletal muscle after resistance exercise. Am J Physiol Endocrinol Metab. 2004;287(1):E1–7.PubMedCrossRefGoogle Scholar
  162. 162.
    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(2):613–24.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Dreyer HC, Fujita S, Glynn EL, et al. Resistance exercise increases leg muscle protein synthesis and mTOR signalling independent of sex. Acta Physiol. 2010;199(1):71–81.CrossRefGoogle Scholar
  164. 164.
    Roschel H, Ugrinowistch C, Barroso R, et al. Effect of eccentric exercise velocity on Akt/mTOR/p70s6k signaling in human skeletal muscle. Appl Physiol Nutr Metab. 2011;36(2):283–90.PubMedCrossRefGoogle Scholar
  165. 165.
    Areta JL, Burke LM, Ross ML, et al. Timing and distribution of protein ingestion during prolonged recovery from resistance exercise alters myofibrillar protein synthesis. J Physiol. 2013;591(9):2319–31.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Glover EI, Oates BR, Tang JE, et al. Resistance exercise decreases eIF2B phosphorylation and potentiates the feeding-induced stimulation of p70s6k1 and rpS6 in young men. Am J Phys Reg Integr Compar Physiol. 2008;295(2):R604–10.CrossRefGoogle Scholar
  167. 167.
    Terzis G, Spengos K, Mascher H, et al. The degree of p70s6k and s6 phosphorylation in human skeletal muscle in response to resistance exercise depends on the training volume. Eur J Appl Physiol. 2010;110(4):835–43.PubMedCrossRefGoogle Scholar
  168. 168.
    Hulmi J, Walker S, Ahtiainen J, et al. Molecular signaling in muscle is affected by the specificity of resistance exercise protocol. Scand J Med Sci Sports. 2012;22(2):240–8.PubMedCrossRefGoogle Scholar
  169. 169.
    Oishi Y, Tsukamoto H, Yokokawa T, et al. Mixed lactate and caffeine compound increases satellite cell activity and anabolic signals for muscle hypertrophy. J Appl Physiol. 2015;118(6):742–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Gundermann DM, Dickinson JM, Fry CS, et al. Inhibition of glycolysis and mTORC1 activation in human skeletal muscle with blood flow restriction exercise. FASEB J. 1076;2012(26):3.Google Scholar
  171. 171.
    Moore DR, Phillips SM, Babraj JA, et al. Myofibrillar and collagen protein synthesis in human skeletal muscle in young men after maximal shortening and lengthening contractions. Am J Physiol Endocrinol Metab. 2005;288(6):E1153–9.PubMedCrossRefGoogle Scholar
  172. 172.
    Cuthbertson DJ, Babraj J, Smith K, et al. Anabolic signaling and protein synthesis in human skeletal muscle after dynamic shortening or lengthening exercise. Am J Physiol Endocrinol Metab. 2006;290(4):E731–8.PubMedCrossRefGoogle Scholar
  173. 173.
    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.PubMedCrossRefGoogle Scholar
  174. 174.
    Rahbek SK, Farup J, Møller AB, et al. Effects of divergent resistance exercise contraction mode and dietary supplementation type on anabolic signalling, muscle protein synthesis and muscle hypertrophy. Amino Acids. 2014;46(10):2377–92.PubMedCrossRefGoogle Scholar
  175. 175.
    Moore DR, Young M, Phillips SM. Similar increases in muscle size and strength in young men after training with maximal shortening or lengthening contractions when matched for total work. Eur J Appl Physiol. 2012;112(4):1587–92.PubMedCrossRefGoogle Scholar
  176. 176.
    Davidsen PK, Gallagher IJ, Hartman JW, et al. High responders to resistance exercise training demonstrate differential regulation of skeletal muscle mRNA expression. J Appl Physiol. 2011;110(2):309–17.PubMedCrossRefGoogle Scholar
  177. 177.
    Phillips SM. A brief review of critical processes in exercise-induced muscular hypertrophy. Sports Med. 2014;44(1):71–7.PubMedCentralCrossRefGoogle Scholar
  178. 178.
    Ogasawara R, Kobayashi K, Tsutaki A, et al. mTOR signaling response to resistance exercise is altered by chronic resistance training and detraining in skeletal muscle. J Appl Physiol. 2013;114(7):934–40.PubMedCrossRefGoogle Scholar
  179. 179.
    Hoffman J, Maresh C, Armstrong L, et al. Effects of off-season and in-season resistance training programs on a collegiate male basketball team. J Hum Muscle Perform. 1991;1(2):48–55.Google Scholar
  180. 180.
    Häkkinen K, Komi PV, Alén M, et al. EMG, muscle fibre and force production characteristics during a 1 year training period in elite weight-lifters. Eur J Appl Physiol Occup Physiol. 1987;56(4):419–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Adam M. Gonzalez
    • 1
  • Jay R. Hoffman
    • 2
  • Jeffrey R. Stout
    • 2
  • David H. Fukuda
    • 2
  • Darryn S. Willoughby
    • 3
  1. 1.Department of Health ProfessionsHofstra UniversityHempsteadUSA
  2. 2.Institute of Exercise Physiology and Wellness, Sport and Exercise ScienceCollege of Education and Human Performance, University of Central FloridaOrlandoUSA
  3. 3.Exercise and Biochemical Nutrition LaboratoryBaylor UniversityWacoUSA

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