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A Review on the Mechanisms of Blood-Flow Restriction Resistance Training-Induced Muscle Hypertrophy

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Abstract

It has traditionally been believed that resistance training can only induce muscle growth when the exercise intensity is greater than 65 % of the 1-repetition maximum (RM). However, more recently, the use of low-intensity resistance exercise with blood-flow restriction (BFR) has challenged this theory and consistently shown that hypertrophic adaptations can be induced with much lower exercise intensities (<50 % 1-RM). Despite the potent hypertrophic effects of BFR resistance training being demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Metabolic stress has been suggested to be a primary factor responsible, and this is theorised to activate numerous other mechanisms, all of which are thought to induce muscle growth via autocrine and/or paracrine actions. However, it is noteworthy that some of these mechanisms do not appear to be mediated to any great extent by metabolic stress but rather by mechanical tension (another primary factor of muscle hypertrophy). Given that the level of mechanical tension is typically low with BFR resistance exercise (<50 % 1-RM), one may question the magnitude of involvement of these mechanisms aligned to the adaptations reported with BFR resistance training. However, despite the low level of mechanical tension, it is plausible that the effects induced by the primary factors (mechanical tension and metabolic stress) are, in fact, additive, which ultimately contributes to the adaptations seen with BFR resistance training. Exercise-induced mechanical tension and metabolic stress are theorised to signal a number of mechanisms for the induction of muscle growth, including increased fast-twitch fibre recruitment, mechanotransduction, muscle damage, systemic and localised hormone production, cell swelling, and the production of reactive oxygen species and its variants, including nitric oxide and heat shock proteins. However, the relative extent to which these specific mechanisms are induced by the primary factors with BFR resistance exercise, as well as their magnitude of involvement in BFR resistance training-induced muscle hypertrophy, requires further exploration.

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References

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

    CAS  PubMed  Google Scholar 

  2. MacDougall JD, Sale DG, Elder GC, et al. Muscle ultrastructural characteristics of elite powerlifters and bodybuilders. Eur J Appl Physiol Occup Physiol. 1982;48(1):117–26.

    CAS  PubMed  Google Scholar 

  3. McCall 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.

    CAS  PubMed  Google Scholar 

  4. 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.

    CAS  PubMed  Google Scholar 

  5. Kraemer WJ, Adams K, Cafarelli E, American College of Sports Medicine, 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  Google Scholar 

  6. Takarada Y, Takazawa H, Sato Y, et al. Effects of resistance exercise combined with moderate vascular occlusion on muscular function in humans. J Appl Physiol. 2000;88(6):2097–106.

    CAS  PubMed  Google Scholar 

  7. Takarada Y, Sato Y, Ishii N. Effects of resistance exercise combined with vascular occlusion on muscle function in athletes. Eur J Appl Physiol. 2002;86(4):308–14.

    PubMed  Google Scholar 

  8. Takarada Y, Tsuruta T, Ishii N. Cooperative effects of exercise and occlusive stimuli on muscular function in low-intensity resistance exercise with moderate vascular occlusion. Jpn J Physiol. 2004;54(6):585–92.

    PubMed  Google Scholar 

  9. Takada S, Okita K, Suga T, et al. Low-intensity exercise can increase muscle mass and strength proportionally to enhanced metabolic stress under ischemic conditions. J Appl Physiol. 2012;113(2):199–205.

    CAS  PubMed  Google Scholar 

  10. Sumide T, Sakuraba K, Sawaki K, et al. Effect of resistance exercise training combined with relatively low vascular occlusion. J Sci Med Sport. 2009;12(1):107–12.

    PubMed  Google Scholar 

  11. Fujita S, Abe T, Drummond MJ, et al. Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis. J Appl Physiol. 2007;103(3):903–10.

    CAS  PubMed  Google Scholar 

  12. Loenneke JP, Pujol TJ. The use of occlusion training to produce muscle hypertrophy. Strength Cond J. 2009;31(3):77–84.

    Google Scholar 

  13. Pope ZK, Willardson JM, Schoenfeld BJ. A brief review: exercise and blood flow restriction. J Strength Cond Res. 2013;27(10):2914–26.

    PubMed  Google Scholar 

  14. Abe T, Kearns CF, Sato Y. Muscle size and strength are increased following walk training with restricted venous blood flow from the leg muscle, Kaatsu-walk training. J Appl Physiol. 2006;100(5):1460–6.

    CAS  PubMed  Google Scholar 

  15. Moore DR, Burgomaster KA, Schofield LM, et al. Neuromuscular adaptations in human muscle following low intensity resistance training with vascular occlusion. Eur J Appl Physiol. 2004;92(4–5):399–406.

    PubMed  Google Scholar 

  16. Kaijser L, Sundberg CJ, Eiken O, et al. Muscle oxidative capacity and work performance after training under local leg ischemia. J Appl Physiol. 1990;69(2):785–7.

    CAS  PubMed  Google Scholar 

  17. Manini TM, Clark BC. Blood flow restricted exercise and skeletal muscle health. Exerc Sports Sci Rev. 2009;37(2):78–85.

    Google Scholar 

  18. Shinohara M, Kouzaki M, Yoshihisa T, et al. Efficacy of tourniquet ischemia for strength training with low resistance. Eur J Appl Physiol Occup Physiol. 1998;77(1–2):189–91.

    CAS  PubMed  Google Scholar 

  19. Takano H, Morita T, Iida H, et al. Hemodynamic and hormonal responses to a short-term low-intensity resistance exercise with the reduction of muscle blood flow. Eur J Appl Physiol. 2005;95(1):65–73.

    CAS  PubMed  Google Scholar 

  20. Loenneke JP, Kearney ML, Thrower AD, et al. The acute response of practical occlusion in the knee extensors. J Strength Cond Res. 2010;24(10):2831–4.

    PubMed  Google Scholar 

  21. Loenneke JP, Fahs CA, Wilson JM, et al. Blood flow restriction: the metabolite/volume threshold theory. Med Hypotheses. 2011;77(5):748–52.

    CAS  PubMed  Google Scholar 

  22. Moritani T, Sherman WM, Shibata M, et al. Oxygen availability and motor unit activity in humans. Eur J Appl Physiol Occup Physiol. 1992;64(6):552–6.

    CAS  PubMed  Google Scholar 

  23. Yasuda T, Brechue WF, Fujita T, et al. Muscle activation during low-intensity muscle contractions with restricted blood flow. J Sports Sci. 2009;27(5):479–89.

    PubMed  Google Scholar 

  24. Takarada Y, Nakamura Y, Aruga S, et al. Rapid increase in plasma growth hormone after low-intensity resistance exercise with vascular occlusion. J Appl Physiol. 2000;88(1):61–5.

    CAS  PubMed  Google Scholar 

  25. Reeves GV, Kraemer RR, Hollander DB, et al. Comparison of hormone responses following light resistance exercise with partial vascular occlusion and moderately difficult resistance exercise without occlusion. J Appl Physiol. 2006;101(6):1616–22.

    CAS  PubMed  Google Scholar 

  26. Loenneke JP, Fahs CA, Rossow LM, et al. The anabolic benefits of venous blood flow restriction training may be induced by muscle cell swelling. Med Hypotheses. 2012;78(1):151–4.

    CAS  PubMed  Google Scholar 

  27. Kawada S, Ishii N. Skeletal muscle hypertrophy after chronic restriction of venous blood flow in rats. Med Sci Sports Exerc. 2005;37(7):1144–50.

    PubMed  Google Scholar 

  28. Suga T, Okita K, Morita N, et al. Intramuscular metabolism during low-intensity resistance exercise with blood flow restriction. J Appl Physiol. 2009;106(4):1119–24.

    CAS  PubMed  Google Scholar 

  29. Goldfarb AH, Garten RS, Chee PD, et al. Resistance exercise effects on blood glutathione status and plasma protein carbonyls: influence of partial vascular occlusion. Eur J Appl Physiol. 2008;104(5):813–9.

    CAS  PubMed  Google Scholar 

  30. Cook SB, Murphy BG, Labarbera KE. Neuromuscular function after a bout of low-load blood flow-restricted exercise. Med Sci Sports Exerc. 2013;45(1):67–74.

    PubMed  Google Scholar 

  31. Schoenfeld BJ. Potential mechanisms for a role of metabolic stress in hypertrophic adaptations to resistance training. Sports Med. 2013;43(3):179–94.

    PubMed  Google Scholar 

  32. Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res. 2010;24(10):2857–72.

    PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. 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.

    CAS  PubMed  Google Scholar 

  35. Kon M, Ikeda T, Homma T, et al. Effects of low-intensity resistance exercise under acute systemic hypoxia on hormonal responses. J Strength Cond Res. 2012;26(3):611–7.

    PubMed  Google Scholar 

  36. Goldberg AL, Etlinger JD, Goldspink DF, et al. Mechanism of work-induced hypertrophy of skeletal muscle. Med Sci Sports. 1975;7(3):185–98.

    CAS  PubMed  Google Scholar 

  37. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Vandenburgh H, Kaufman S. In vitro model for stretch-induced hypertrophy of skeletal muscle. Science. 1979;203(4377):265–8.

    CAS  PubMed  Google Scholar 

  39. Goldspink G. Cellular and molecular aspects of muscle growth, adaptation and ageing. Gerodontology. 1998;15(1):35–43.

    CAS  PubMed  Google Scholar 

  40. Zou K, Meador BM, Johnson B, et al. The α7β1-integrin increases muscle hypertrophy following multiple bouts of eccentric exercise. J Appl Physiol. 2011;111(4):1134–41.

    CAS  PubMed  Google Scholar 

  41. Adams GR. Invited review: autocrine/paracrine IGF-I and skeletal muscle adaptation. J Appl Physiol. 2002;93(3):1159–67.

    CAS  PubMed  Google Scholar 

  42. Tatsumi R, Liu X, Pulido A, et al. Satellite cell activation in stretched skeletal muscle and the role of nitric oxide and hepatocyte growth factor. Am J Physiol Cell Physiol. 2006;290(6):C1487–94.

    CAS  PubMed  Google Scholar 

  43. Uchiyama S, Tsukamoto H, Yoshimura S, et al. Relationship between oxidative stress in muscle tissue and weight-lifting-induced muscle damage. Pflugers Arch. 2006;452(1):109–16.

    CAS  PubMed  Google Scholar 

  44. 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.

    CAS  PubMed  Google Scholar 

  45. 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.

    CAS  PubMed  Google Scholar 

  46. Suga T, Okita K, Morita N, et al. Dose effect on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction. J Appl Physiol. 2010;108(6):1563–7.

    PubMed  Google Scholar 

  47. Goto K, Ishii N, Kizuka T, et al. The impact of metabolic stress on hormonal responses and muscular adaptations. Med Sci Sports Exerc. 2005;37(6):955–63.

    CAS  PubMed  Google Scholar 

  48. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev. 2005;33(3):114–9.

    PubMed  Google Scholar 

  49. Schiaffino S, Dyar KA, Ciciliot S, et al. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 2013;280(17):4292–314.

    Google Scholar 

  50. Hornberger TA, Esser KA. Mechanotransduction and the regulation of protein synthesis in skeletal muscle. Proc Nutr Soc. 2004;63(2):331–5.

    CAS  PubMed  Google Scholar 

  51. 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.

    CAS  PubMed  Google Scholar 

  52. Nielsen AR, Pedersen BK. The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15. Appl Physiol Nutr Metab. 2007;32(5):833–9.

    CAS  PubMed  Google Scholar 

  53. Quinn LS. Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. J Anim Sci. 2008;86(Suppl 14):E75–83.

    CAS  PubMed  Google Scholar 

  54. Serrano AL, Baeza-Raja B, Perdiguero E, et al. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 2008;7(1):33–44.

    CAS  PubMed  Google Scholar 

  55. Sorichter S, Mair J, Koller A, et al. Skeletal troponin I as a marker of exercise-induced muscle damage. J Appl Physiol. 1997;83(4):1076–82.

    CAS  PubMed  Google Scholar 

  56. Hather BM, Tesch PA, Buchanan P, et al. Influence of eccentric actions on skeletal muscle adaptations to resistance training. Acta Physiol Scand. 1991;143(2):177–85.

    CAS  PubMed  Google Scholar 

  57. Roig M, O’Brien K, Kirk G, et al. The effects of eccentric versus concentric resistance training on muscle strength and mass in healthy adults: a systematic review with meta-analysis. Br J Sports Med. 2009;43(8):556–68.

    CAS  PubMed  Google Scholar 

  58. McHugh MP, Connolly DA, Eston RG, et al. Exercise-induced muscle damage and potential mechanisms for the repeated bout effect. Sports Med. 1999;27(3):157–70.

    CAS  PubMed  Google Scholar 

  59. Thiebaud RS, Yasuda T, Loenneke JP, et al. Effects of low-intensity concentric and eccentric exercise combined with blood flow restriction on indices of exercise-induced muscle damage. Interv Med Appl Sci. 2013;5(2):53–9.

    PubMed Central  PubMed  Google Scholar 

  60. Thiebaud RS, Loenneke JP, Fahs CA, et al. Muscle damage after low-intensity eccentric contractions with blood flow restriction. Acta Physiol Hung. 2014;101(2):150–7.

    CAS  PubMed  Google Scholar 

  61. Umbel JD, Hoffman RL, Dearth DJ, et al. Delayed-onset muscle soreness induced by low-load blood flow-restricted exercise. Eur J Appl Physiol. 2009;107(6):687–95.

    PubMed  Google Scholar 

  62. Fry CS, Glynn EL, Drummond MJ, et al. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men. J Appl Physiol. 2010;108(5):1199–209.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Patterson SD, Leggate M, Nimmo MA, et al. Circulating hormone and cytokine response to low-load resistance training with blood flow restriction in older men. Eur J Appl Physiol. 2013;113(3):713–9.

    CAS  PubMed  Google Scholar 

  64. Hellsten Y, Frandsen U, Orthenblad N, et al. Xanthine oxidase in human skeletal muscle following eccentric exercise: a role in inflammation. J Physiol. 1997;498(Pt 1):239–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Manini TM, Yarrow JF, Buford TW, et al. Growth hormone responses to acute resistance exercise with vascular restriction in young and old men. Growth Horm IGF Res. 2012;22(5):167–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. 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.

    CAS  PubMed  Google Scholar 

  67. 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.

    CAS  PubMed  Google Scholar 

  68. 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(Pt 21):5239–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Owino V, Yang SY, Goldspink G. Age-related loss of skeletal muscle function and the inability to express the autocrine form of insulin-like growth factor-1 (MGF) in response to mechanical overload. FEBS Lett. 2001;505(2):259–63.

    CAS  PubMed  Google Scholar 

  72. Philippou A, Papageorgiou E, Bogdanis G, et al. Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: characterization of the MGF Epeptide actions in vitro. Vivo. 2009;23(4):567–75.

    CAS  Google Scholar 

  73. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Goldspink G, Wessner B, Bachl N. Growth factors, muscle function and doping. Curr Opin Pharmacol. 2008;8(3):352–7.

    CAS  PubMed  Google Scholar 

  75. Goldspink G. Mechanical signals, IGF-I gene splicing, and muscle adaptation. Physiology (Bethesda). 2005;20:232–8.

    CAS  Google Scholar 

  76. Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 2008;23:160–70.

    CAS  PubMed  Google Scholar 

  77. Barton ER. Viral expression of insulin-like growth factor-I isoforms promotes different responses in skeletal muscle. J Appl Physiol. 2006;100(6):1778–84.

    CAS  PubMed  Google Scholar 

  78. Tidball JG. Mechanical signal transduction in skeletal muscle growth and adaptation. J Appl Physiol. 2005;98(5):1900–8.

    CAS  PubMed  Google Scholar 

  79. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett. 2002;522(1–3):156–60.

    CAS  PubMed  Google Scholar 

  80. Hill M, Wernig A, Goldspink G. Muscle satellite (stem) cell activation during local tissue injury and repair. J Anat. 2003;203(1):89–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Lang F, Busch GL, Ritter M, et al. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78(1):247–306.

    CAS  PubMed  Google Scholar 

  82. Lang F. Mechanisms and significance of cell volume regulation. J Am Coll Nutr. 2007;26(Suppl 5):613S–23S.

    CAS  PubMed  Google Scholar 

  83. Low SY, Rennie MJ, Taylor PM. Signaling elements involved in amino acid transport responses to altered muscle cell volume. FASEB J. 1997;11(13):1111–7.

    CAS  PubMed  Google Scholar 

  84. Clarke MS, Feeback DL. Mechanical load induces sarcoplasmic wounding and FGF release in differentiated human skeletal muscle cultures. FASEB J. 1996;10(4):502–9.

    CAS  PubMed  Google Scholar 

  85. Lambert IH, Hoffmann EK, Pedersen SF. Cell volume regulation: physiology and pathophysiology. Acta Physiol (Oxf). 2008;194(4):255–82.

    CAS  Google Scholar 

  86. Schliess F, Richter L, vom Dahl S, et al. Cell hydration and mTOR-dependent signalling. Acta Physiol (Oxf). 2006;187(1–2):223–9.

    CAS  Google Scholar 

  87. Finkenzeller G, Newsome W, Lang F, et al. Increase of c-jun mRNA upon hypo-osmotic cell swelling of rat hepatoma cells. FEBS Lett. 1994;340(3):163–6.

    CAS  PubMed  Google Scholar 

  88. Schliess F, Schreiber R, Häussinger D. Activation of extracellular signal-regulated kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells. Biochem J. 1995;309(Pt 1):13–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Dangott B, Schultz E, Mozdziak PE. Dietary creatine monohydrate supplementation increases satellite cell mitotic activity during compensatory hypertrophy. Int J Sports Med. 2000;21(1):13–6.

    CAS  PubMed  Google Scholar 

  90. Gundermann D, Fry C, Dickinson J, et al. Reactive hyperaemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise. J Appl Physiol. 2012;112(9):1520–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Alessio HM, Hagerman AE, Fulkerson BK, et al. Generation of reactive oxygen species after exhaustive aerobic and isometric exercise. Med Sci Sports Exerc. 2000;32(9):1576–81.

    CAS  PubMed  Google Scholar 

  92. Jackson MJ. Free radicals generated by contracting muscle: by-products of metabolism or key regulators of muscle function? Free Radic Biol Med. 2008;44(2):132–41.

    CAS  PubMed  Google Scholar 

  93. Gomez-Cabrera MC, Domenech E, Viña J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med. 2008;44(2):126–31.

    CAS  PubMed  Google Scholar 

  94. Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann NY Acad Sci. 2006;1067:425–35.

    CAS  PubMed  Google Scholar 

  95. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279(6):L1005–28.

    CAS  PubMed  Google Scholar 

  96. Suzuki YJ, Ford GD. Redox regulation of signal transduction in cardiac and smooth muscle. J Mol Cell Cardiol. 1999;31(2):345–53.

    CAS  PubMed  Google Scholar 

  97. Wernbom M, Jarrebring R, Andreasson MA, et al. Acute effects of blood flow restriction on muscle fatiguing dynamic knee extensions at low load. J Strength Cond Res. 2009;23(8):2389–95.

    PubMed  Google Scholar 

  98. Korthuis RJ, Granger DN, Townsley MI, et al. The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability. Circ Res. 1985;57(4):599–609.

    CAS  PubMed  Google Scholar 

  99. Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol. 2007;102(6):2379–88.

    CAS  PubMed  Google Scholar 

  100. Nakane M, Schmidt HH, Pollock JS, et al. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle. FEBS Lett. 1993;316(2):175–80.

    CAS  PubMed  Google Scholar 

  101. Kobzik L, Reid MB, Bredt DS, et al. Nitric oxide in skeletal muscle. Nature. 1994;372(6506):546–8.

    CAS  PubMed  Google Scholar 

  102. Silvagno F, Xia H, Bredt DS. Neuronal nitric-oxide synthase-mu, an alternatively spliced isoform expressed in differentiated skeletal muscle. J Biol Chem. 1996;271(19):11204–8.

    CAS  PubMed  Google Scholar 

  103. Anderson JE. A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells. Mol Biol Cell. 2000;11(5):1859–974.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Ito N, Ruegg UT, Kudo A, et al. Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy. Nat Med. 2013;19(1):101–6.

    CAS  PubMed  Google Scholar 

  105. Tatsumi R, Hattori A, Ikeuchi Y, et al. Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide. Mol Biol Cell. 2002;13(8):2909–18.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Hunt JE, Walton LA, Ferguson RA. Brachial artery modifications to blood flow-restricted handgrip training and detraining. J Appl Physiol. 2012;112(6):956–61.

    PubMed  Google Scholar 

  107. Hunt JE, Galea D, Tufft G, et al. Time course of regional vascular adaptations to low load resistance training with blood flow restriction. J Appl Physiol. 2013;115(3):403–11.

    PubMed  Google Scholar 

  108. Rudic RD, Shesely EG, Maeda N, et al. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998;101(4):731–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Casey DP, Joyner MJ. NOS inhibition blunts and delays the compensatory dilation in hypoperfused contracting human muscles. J Appl Physiol. 2009;107(6):1685–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Casey DP, Madery BD, Curry TB, et al. Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise. J Physiol. 2010;588(Pt 2):373–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Bailey TG, Birk GK, Cable NT, et al. Remote ischemic preconditioning prevents reduction in brachial artery flow-mediated dilation after strenuous exercise. Am J Physiol Heart Circ Physiol. 2012;303(5):H533–8.

    CAS  PubMed  Google Scholar 

  112. He X, Zhao M, Bi XY, et al. Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS. Lab Invest. 2013;93(2):168–80.

    CAS  PubMed  Google Scholar 

  113. Kimura M, Ueda K, Goto C, et al. Repetition of ischemic preconditioning augments endothelium-dependent vasodilation in humans: role of endothelium-derived nitric oxide and endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2007;27(6):1403–10.

    CAS  PubMed  Google Scholar 

  114. Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998;80(2):183–201.

    CAS  PubMed  Google Scholar 

  115. Simar D, Malatesta D, Badiou S, et al. Physical activity modulates heat shock protein-72 expression and limits oxidative damage accumulation in a healthy elderly population aged 60–90 years. J Gerontol A Biol Sci Med Sci. 2007;62(12):1413–9.

    PubMed  Google Scholar 

  116. Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol. 2002;92(5):2177–86.

    CAS  PubMed  Google Scholar 

  117. Meyer RA. Does blood flow restriction enhance hypertrophic signaling in skeletal muscle? J Appl Physiol. 2006;100(5):1443–4.

    PubMed  Google Scholar 

  118. Sundberg CJ. Exercise and training during graded leg ischaemia in healthy man with special reference to effects on skeletal muscle. Acta Physiol Scand. 1994;615:1–50.

    CAS  Google Scholar 

  119. Yasuda T, Abe T, Brechue WF, et al. Venous blood gas and metabolite response to low-intensity muscle contractions with external limb compression. Metabolism. 2010;59(10):1510–9.

    CAS  PubMed  Google Scholar 

  120. Michel RN, Dunn SE, Chin ER. Cacineurin and skeletal muscle growth. Proc Nutr Soc. 2004;63(2):341–9.

    CAS  PubMed  Google Scholar 

  121. Kacin A, Strazar K. Frequent low-load ischemic resistance exercise to failure enhances muscle oxygen delivery and endurance capacity. Scan J Med Sci Sports. 2011;21(6):e231–41.

    CAS  Google Scholar 

  122. Wernbom M, Apro W, Paulsen G, et al. Acute low-load resistance exercise with and without blood flow restriction increased protein signalling and number of satellite cells in human skeletal muscle. Eur J Appl Physiol. 2013;113(12):2953–65.

    CAS  PubMed  Google Scholar 

  123. 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.

    CAS  PubMed  Google Scholar 

  124. O’Neil TK, Duffy LR, Frey JW, et al. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions. J Physiol. 2009;587(Pt 14):3691–701.

    PubMed Central  PubMed  Google Scholar 

  125. Reynolds TH, Bodine S, Lawrence JC. Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem. 2002;277(20):17657–62.

    CAS  PubMed  Google Scholar 

  126. Wang X, Proud CG. The mTOR pathway in the control of protein synthesis. Physiology. 2006;21:362–9.

    CAS  PubMed  Google Scholar 

  127. Lee SJ, McPherron AC. Myostatin and the control of skeletal muscle mass. Curr Opin Genet Dev. 1999;9(5):604–7.

    CAS  PubMed  Google Scholar 

  128. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA. 2001;98(16):9306–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94(23):12457–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 2002;109(5):595–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. McCroskery S, Thomas M, Maxwell L, et al. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol. 2003;162(6):1135–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Rebbapragada A, Benchabane H, Wrana JL, et al. Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol. 2003;23(20):7230–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Lin J, Arnold HB, Della-Fera MA, et al. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun. 2002;291(3):701–6.

    CAS  PubMed  Google Scholar 

  134. Ríos R, Carneiro I, Arce VM, et al. Myostatin regulates cell survival during C2C12 myogenesis. Biochem Biophys Res Commun. 2001;280(2):561–6.

    PubMed  Google Scholar 

  135. McPherron AC, Lawler AM, Lee SJ. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet. 1999;22(3):260–4.

    CAS  PubMed  Google Scholar 

  136. Trendelenburg AU, Meyer A, Rohner D, et al. Myostatin reduces Akt/TORC1/p70S6 K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009;296(6):C1258–70.

    CAS  PubMed  Google Scholar 

  137. Drummond MJ, Fujita S, Abe T, et al. Human muscle gene expression following resistance exercise and blood flow restriction. Med Sci Sports Exerc. 2008;40(4):691–8.

    CAS  PubMed  Google Scholar 

  138. Laurentino GC, Ugrinowitsch C, Roschel H, et al. Strength training with blood flow restriction diminishes myostatin gene expression. Med Sci Sports Exerc. 2012;44(3):406–12.

    CAS  PubMed  Google Scholar 

  139. Sartori R, Milan G, Patron M, et al. Smad2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol Cell Physiol. 2009;296(6):C1248–57.

    CAS  PubMed  Google Scholar 

  140. Welle S, Burgess K, Mehta S. Stimulation of skeletal muscle myofibrillar protein synthesis, p70 S6 kinase phosphorylation, and ribosomalprotein S6 phosphorylation by inhibition of myostatin in mature mice. Am J Physiol Endocrinol Metab. 2009;296(3):E567–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Raffaello A, Milan G, Masiero E, et al. JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. J Cell Biol. 2010;191(1):101–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117(3):399–412.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Stitt TN, Drujan D, Clarke BA, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 2004;14(3):395–403.

    CAS  PubMed  Google Scholar 

  144. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857–68.

    CAS  PubMed  Google Scholar 

  145. Ramaswamy S, Nakamura N, Sansal I, et al. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2002;2(1):81–91.

    CAS  PubMed  Google Scholar 

  146. Mammucari C, Milan G, Romanello V, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458–71.

    CAS  PubMed  Google Scholar 

  147. Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472–83.

    CAS  PubMed  Google Scholar 

  148. Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med. 1996;335(25):1897–905.

    CAS  PubMed  Google Scholar 

  149. Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol. 2013;49(1):59–68.

    PubMed Central  PubMed  Google Scholar 

  150. Bodine SC, Latres E, Baumhueter S, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 2001;294(5547):1704–8.

    CAS  PubMed  Google Scholar 

  151. Gomes MD, Lecker SH, Jagoe RT, et al. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA. 2001;98(25):14440–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Clarke BA, Drujan D, Willis MS, et al. The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab. 2007;6(5):376–85.

    CAS  PubMed  Google Scholar 

  153. Cohen S, Brault JJ, Gygi SP, et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol. 2009;185(6):1083–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Li HH, Willis MS, Lockyer P, et al. Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. J Clin Invest. 2007;117(11):3211–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Herningtyas EH, Okimura Y, Handayaningsih AE, et al. Branched-chain amino acids and arginine suppress MaFbx/atrogin-1 mRNA expression via mTOR pathway in C2C12 cell line. Biochim Biophys Acta. 2008;1780(10):1115–20.

    CAS  PubMed  Google Scholar 

  156. Shimizu N, Yoshikawa N, Ito N, et al. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 2011;13(2):170–82.

    CAS  PubMed  Google Scholar 

  157. Waddell DS, Baehr LM, van den Brandt J, et al. The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab. 2008;295(4):E785–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Zhao W, Qin W, Pan J, et al. Dependence of dexamethasone-induced Akt/FOXO1 signaling, upregulation of MAFbx, and protein catabolism upon the glucocorticoid receptor. Biochem Biophys Res Commun. 2009;378(3):668–72.

    CAS  PubMed  Google Scholar 

  159. Gottlieb RA, Mentzer RM. Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol. 2010;72:45–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Nishida Y, Arakawa S, Fujitani K, et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature. 2009;461(7264):654–8.

    CAS  PubMed  Google Scholar 

  161. Romanello V, Guadagnin E, Gomes L, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010;29(10):1774–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Ciciliot S, Schiaffino S. Regeneration of mammalian skeletal muscle. Basic mechanisms and clinical implications. Curr Pharm Des. 2010;16(8):906–14.

    CAS  PubMed  Google Scholar 

  163. Schiaffino S, Bormioli SP, Aloisi M. Cell proliferation in rat skeletal muscle during early stages of compensatory hypertrophy. Virchows Arch B Cell Pathol. 1972;11(3):268–73.

    CAS  PubMed  Google Scholar 

  164. Nielsen JL, Aagaard P, Bech RD, et al. Proliferation of myogenic stem cells in human skeletal muscle in response to low-load resistance training with blood flow restriction. J Physiol. 2012;590(Pt 17):4351–61.

    CAS  PubMed Central  PubMed  Google Scholar 

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No funding was provided in the preparation of this review, and the authors have no conflicts of interest that are directly relevant to the contents of the review.

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Pearson, S.J., Hussain, S.R. A Review on the Mechanisms of Blood-Flow Restriction Resistance Training-Induced Muscle Hypertrophy. Sports Med 45, 187–200 (2015). https://doi.org/10.1007/s40279-014-0264-9

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