It is well established that regimented resistance training can promote increases in muscle hypertrophy. The prevailing body of research indicates that mechanical stress is the primary impetus for this adaptive response and studies show that mechanical stress alone can initiate anabolic signalling. Given the dominant role of mechanical stress in muscle growth, the question arises as to whether other factors may enhance the post-exercise hypertrophic response. Several researchers have proposed that exercise-induced metabolic stress may in fact confer such an anabolic effect and some have even suggested that metabolite accumulation may be more important than high force development in optimizing muscle growth. Metabolic stress pursuant to traditional resistance training manifests as a result of exercise that relies on anaerobic glycolysis for adenosine triphosphate production. This, in turn, causes the subsequent accumulation of metabolites, particularly lactate and H+. Acute muscle hypoxia associated with such training methods may further heighten metabolic buildup. Therefore, the purpose of this paper will be to review the emerging body of research suggesting a role for exercise-induced metabolic stress in maximizing muscle development and present insights as to the potential mechanisms by which these hypertrophic adaptations may occur. These mechanisms include increased fibre recruitment, elevated systemic hormonal production, alterations in local myokines, heightened production of reactive oxygen species and cell swelling. Recommendations are provided for potential areas of future research on the subject.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Goldberg AL, Etlinger JD, Goldspink DF, et al. Mechanism of work-induced hypertrophy of skeletal muscle. Med Sci Sports. 1975 Fall;7(3):185–98.
Witkowski S, Lovering RM, Spangenburg EE. High-frequency electrically stimulated skeletal muscle contractions increase p70s6k phosphorylation independent of known IGF-I sensitive signaling pathways. FEBS Lett. 2010;584(13):2891–5.
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.
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.
Vandenburgh H, Kaufman S. In vitro model for stretch-induced hypertrophy of skeletal muscle. Science. 1979;203(4377):265–8.
Miyazaki M, McCarthy JJ, Fedele MJ, et al. Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling. J Physiol. 2011;589(Pt 7):1831–46.
Toigo M, Boutellier U. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur J Appl Physiol. 2006;97(6):643–63.
Mayhew DL, Hornberger TA, Lincoln HC, et al. Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy. J Physiol. 2011;589(Pt 12):3023–37.
Tidball JG. Mechanical signal transduction in skeletal muscle growth and adaptation. J Appl Physiol. 2005;98(5):1900–8.
Bassel-Duby R, Olson EN. Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem. 2006;75:19–37.
Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. J Appl Physiol. 2009;106(4):1367–73.
Glass DJ. Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol. 2005;37(10):1974–84.
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 USA. 2006;103(12):4741–6.
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.
Lehman N, Ledford B, Di Fulvio M, et al. Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR. FASEB J. 2007;21(4):1075–87.
Rooney KJ, Herbert RD, Balnave RJ. Fatigue contributes to the strength training stimulus. Med Sci Sports Exerc. 1994;26(9):1160–4.
Schott J, McCully K, Rutherford OM. The role of metabolites in strength training. II. Short versus long isometric contractions. Eur J Appl Physiol Occup Physiol. 1995;71(4):337–41.
Smith RC, Rutherford OM. The role of metabolites in strength training. I. A comparison of eccentric and concentric contractions. Eur J Appl Physiol Occup Physiol. 1995;71(4):332–6.
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.
Folland JP, Irish CS, Roberts JC, et al. Fatigue is not a necessary stimulus for strength gains during resistance training. Br J Sports Med. 2002;36(5):370–3.
Tesch PA, Colliander EB, Kaiser P. Muscle metabolism during intense, heavy-resistance exercise. Eur J Appl Physiol Occup Physiol. 1986;55(4):362–6.
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.
Pierce JR, Clark BC, Ploutz-Snyder LL, et al. Growth hormone and muscle function responses to skeletal muscle ischemia. J Appl Physiol. 2006;101(6):1588–95.
Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res. 2010;24(10):2857–72.
Fry AC. The role of resistance exercise intensity on muscle fibre adaptations. Sports Med. 2004;34(10):663–79.
Lambert CP, Flynn MG. Fatigue during high-intensity intermittent exercise: application to bodybuilding. Sports Med. 2002;32(8):511–22.
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.
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.
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.
Katch VL, Katch FI, Moffatt R, et al. Muscular development and lean body weight in body builders and weight lifters. Med Sci Sports Exerc. 1980;12(5):340–4.
Schmidtbleicher D, Buehrle M. Neuronal adaptation and increase of cross-sectional area studying different strength training methods. In: Jonsson GB, editor. Biomechanics X-B volume 6-B. Champaign: Human Kinetics; 1987. p. 615–20.
Choi J, Takahashi H, Itai Y. The difference between effects of ‘power-up type’ and ‘bulk-up type’ strength training exercises: with special reference to muscle cross-sectional area. Jpn J Phys Fitness Sports Med. 1998;47(1):119–29.
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.
Campos GER, 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.
Robbins DW, Goodale TL, Docherty D, et al. The effects of load and training pattern on acute neuromuscular responses in the upper body. J Strength Cond Res. 2010;24(11):2996–3007.
MacDougall JD, Ray S, Sale DG, et al. Muscle substrate utilization and lactate production. Can J Appl Physiol. 1999;24(3):209–15.
Tamaki T, Uchiyama S, Tamura T, et al. Changes in muscle oxygenation during weight-lifting exercise. Eur J Appl Physiol Occup Physiol. 1994;68(6):465–9.
Suga T, Okita K, Morita N, Yokota T, 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.
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.
Loenneke JP, Wilson JM, Marin PJ, et al. Low intensity blood flow restriction training: a meta-analysis. Eur J Appl Physiol. 2012;112(5):1849–59.
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.
Loenneke JP, Wilson GJ, Wilson JM. A mechanistic approach to blood flow occlusion. Int J Sports Med. 2010;31(1):1–4.
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.
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.
Nishimura A, Sugita M, Kato K, et al. Hypoxia increases muscle hypertrophy induced by resistance training. Int J Sports Physiol Perform. 2010;5(4):497–508.
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.
Gordon SE, Kraemer WJ, Vos NH, et al. Effect of acid-base balance on the growth hormone response to acute high-intensity cycle exercise. J Appl Physiol. 1994;76(2):821–9.
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.
Henneman E, Somjen G, Carpenter DO. Functional significance of cell size in spinal motoneurons. J Neurophysiol. 1965;28:560–80.
Kraemer WJ, Ratamess NA. Fundamentals of resistance training: progression and exercise prescription. Med Sci Sports Exerc. 2004;36(4):674–88.
Houtman CJ, Stegeman DF, Van Dijk JP, et al. Changes in muscle fiber conduction velocity indicate recruitment of distinct motor unit populations. J Appl Physiol. 2003;95(3):1045–54.
Sahlin K, Soderlund K, Tonkonogi M, et al. Phosphocreatine content in single fibers of human muscle after sustained submaximal exercise. Am J Physiol. 1997;273(1 Pt 1):C172–8.
Vollestad NK, Vaage O, Hermansen L. Muscle glycogen depletion patterns in type I and subgroups of type II fibres during prolonged severe exercise in man. Acta Physiol Scand. 1984;122(4):433–41.
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.
Ingemann-Hansen T, Halkjaer-Kristensen J, Halskov O. Skeletal muscle phosphagen and lactate concentrations in ischaemic dynamic exercise. Eur J Appl Physiol Occup Physiol. 1981;46(3):261–70.
Loenneke JP, Fahs CA, Wilson JM, et al. Blood flow restriction: the metabolite/volume threshold theory. Med Hypotheses. 2011;77(5):748–52.
Meyer RA. Does blood flow restriction enhance hypertrophic signaling in skeletal muscle? J Appl Physiol. 2006;100(5):1443–4.
Miller KJ, Garland SJ, Ivanova T, et al. Motor-unit behavior in humans during fatiguing arm movements. J Neurophysiol. 1996;75(4):1629–36.
Debold EP. Recent insights into the molecular basis of muscular fatigue. Med Sci Sports Exerc. 2012;44(8):1440–52.
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.
Sundberg CJ. Exercise and training during graded leg ischaemia in healthy man with special reference to effects on skeletal muscle. Acta Physiol Scand Suppl. 1994;615:1–50.
Yasuda T, Abe T, Sato Y, et al. Muscle fiber cross-sectional area is increased after two weeks of twice daily KAATSU-resistance training. Int J KAATSU Train Res. 2005;1(2):65–70.
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.
Manini TM, Clark BC. Blood flow restricted exercise and skeletal muscle health. Exerc Sport Sci Rev. 2009;37(2):78–85.
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.
Crewther B, Keogh J, Cronin J, et al. Possible stimuli for strength and power adaptation: acute hormonal responses. Sports Med. 2006;36(3):215–38.
Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med. 2005;35(4):339–61.
Haddad F, Adams GR. Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles. J Appl Physiol. 2004;96(1):203–10.
Stewart CE, Pell JM. Point:Counterpoint: IGF is/is not the major physiological regulator of muscle mass. Point: IGF is the major physiological regulator of muscle mass. J Appl Physiol. 2010;108(6):1820,1; discussion 1823-4; author reply 1832.
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.
Kostek MC, Delmonico MJ, Reichel JB, et al. Muscle strength response to strength training is influenced by insulin-like growth factor 1 genotype in older adults. J Appl Physiol. 2005;98(6):2147–54.
Philippou A, Papageorgiou E, Bogdanis G, et al. Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: characterization of the MGF E peptide actions in vitro. In Vivo. 2009;23(4):567–75.
Goldspink G. Mechanical signals, IGF-I gene splicing, and muscle adaptation. Physiology (Bethesda). 2005;20:232–8.
Velloso CP, Harridge SD. Insulin-like growth factor-I E peptides: implications for aging skeletal muscle. Scand J Med Sci Sports. 2010;20(1):20–7.
Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol. 2008;154(3):557–68.
Timmons JA. Variability in training-induced skeletal muscle adaptation. J Appl Physiol. 2011;110(3):846–53.
Petrella JK, Kim J, Mayhew DL, et al. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol. 2008;104(6):1736–42.
O’Connor RS, Pavlath GK. Point:counterpoint: satellite cell addition is/is not obligatory for skeletal muscle hypertrophy. J Appl Physiol. 2007;103(3):1099–100.
McCarthy JJ, Esser KA. Counterpoint: satellite cell addition is not obligatory for skeletal muscle hypertrophy. J Appl Physiol. 2007;103:1100–2.
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.
Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 2008;23:160–70.
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.
Bamman MM, Petrella JK, Kim JS, et al. Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans. J Appl Physiol. 2007;102(6):2232–9.
Hill M, Wernig A, Goldspink G. Muscle satellite (stem) cell activation during local tissue injury and repair. J Anat. 2003;203(1):89–99.
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.
Philippou A, Maridaki M, Halapas A, et al. The role of the insulin-like growth factor 1 (IGF-1) in skeletal muscle physiology. In Vivo. 2007;21(1):45–54.
Rubin MR, Kraemer WJ, Maresh CM, et al. High-affinity growth hormone binding protein and acute heavy resistance exercise. Med Sci Sports Exerc. 2005;37(3):395–403.
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.
Abe T, Yasuda T, Midorikawa T, et al. Skeletal muscle size and circulating IGF-1 are increased after two weeks of twice daily KAATSU resistance training. Int J Kaatsu Train Res. 2005;1:6–12.
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.
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.
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.
Buresh R, Berg K, French J. The effect of resistive exercise rest interval on hormonal response, strength, and hypertrophy with training. J Strength Cond Res. 2009;23(1):62–71.
Kadi F. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle: a basis for illegal performance enhancement. Br J Pharmacol. 2008;154(3):522–8.
Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. J Endocrinol. 2001;170(1):27–38.
Zhao W, Pan J, Zhao Z, et al. Testosterone protects against dexamethasone-induced muscle atrophy, protein degradation and MAFbx upregulation. J Steroid Biochem Mol Biol. 2008;110(1–2):125–9.
Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 1995;269(5 Pt 1):E820–6.
Vingren JL, Kraemer WJ, Ratamess NA, et al. Testosterone physiology in resistance exercise and training: the up-stream regulatory elements. Sports Med. 2010;40(12):1037–53.
Sculthorpe N, Solomon AM, Sinanan AC, et al. Androgens affect myogenesis in vitro and increase local IGF-1 expression. Med Sci Sports Exerc. 2012;44(4):610–5.
Sinha-Hikim I, Cornford M, Gaytan H, et al. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab. 2006;91(8):3024–33.
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.
Tremblay MS, Copeland JL, Van Helder W. Effect of training status and exercise mode on endogenous steroid hormones in men. J Appl Physiol. 2004;96(2):531–9.
Kraemer WJ, Fry AC, Warren BJ, et al. Acute hormonal responses in elite junior weightlifters. Int J Sports Med. 1992;13(2):103–9.
Loenneke JP, Wilson JM, Pujol TJ, et al. Acute and chronic testosterone response to blood flow restricted exercise. Horm Metab Res. 2011;43(10):669–73.
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.
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.
Smilios I, Pilianidis T, Karamouzis M, et al. Hormonal responses after various resistance exercise protocols. Med Sci Sports Exerc. 2003;35(4):644–54.
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.
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.
Viru M, Jansson E, Viru A, et al. Effect of restricted blood flow on exercise-induced hormone changes in healthy men. Eur J Appl Physiol Occup Physiol. 1998;77(6):517–22.
Vierck J, O’Reilly B, Hossner K, et al. Satellite cell regulation following myotrauma caused by resistance exercise. Cell Biol Int. 2000;24(5):263–72.
Doessing S, Heinemeier KM, Holm L, et al. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis. J Physiol. 2010;588(Pt 2):341–51.
Sotiropoulos A, Ohanna M, Kedzia C, et al. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci USA. 2006;103(19):7315–20.
Aperghis M, Velloso CP, Hameed M, et al. Serum IGF-I levels and IGF-I gene splicing in muscle of healthy young males receiving rhGH. Growth Horm IGF Res. 2009;19(1):61–7.
Ehrnborg C, Rosen T. Physiological and pharmacological basis for the ergogenic effects of growth hormone in elite sports. Asian J Androl. 2008;10(3):373–83.
Kraemer WJ, Dunn-Lewis C, Comstock BA, et al. Growth hormone, exercise, and athletic performance: a continued evolution of complexity. Curr Sports Med Rep. 2010;9(4):242–52.
Phillips SM. Physiologic and molecular bases of muscle hypertrophy and atrophy: impact of resistance exercise on human skeletal muscle (protein and exercise dose effects). Appl Physiol Nutr Metab. 2009;34(3):403–10.
West DW, Phillips SM. Anabolic processes in human skeletal muscle: restoring the identities of growth hormone and testosterone. Phys Sportsmed. 2010;38(3):97–104.
Lange KH, Andersen JL, Beyer N, et al. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab. 2002;87(2):513–23.
Yarasheski KE, Campbell JA, Smith K, et al. Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol. 1992;262(3 Pt 1):E261–7.
Yarasheski KE, Zachwieja JJ, Campbell JA, et al. Effect of growth hormone and resistance exercise on muscle growth and strength in older men. Am J Physiol. 1995;268(2 Pt 1):E268–76.
Nindl BC, Hymer WC, Deaver DR, et al. Growth hormone pulsatility profile characteristics following acute heavy resistance exercise. J Appl Physiol. 2001;91(1):163–72.
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.
Coffey VG, Shield A, Canny BJ, et al. Interaction of contractile activity and training history on mRNA abundance in skeletal muscle from trained athletes. Am J Physiol Endocrinol Metab. 2006;290(5):E849–55.
Madarame H, Neya M, Ochi E, et al. Cross-transfer effects of resistance training with blood flow restriction. Med Sci Sports Exerc. 2008;40(2):258–63.
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.
Ronnestad 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.
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.
Quinn LS. Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. J Anim Sci. 2008;86(14 Suppl.):E75–83.
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.
Pedersen BK, Edward F. Adolph distinguished lecture: muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol. 2009;107(4):1006–14.
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.
Fujita T, Brechue WF, Kurita K, et al. Increased muscle volume and strength following six days of low-intensity resistance training with restricted muscle blood flow. Int J Kaatsu Train Res. 2008;4:1–8.
Abe T, Beekley MD, Hinata S, et al. Day-to-day change in muscle strength and MRI-measured skeletal muscle size during 7 days KAATSU resistance training: a case study. Int J Kaatsu Train Res. 2005;1:71–6.
Roth SM, Walsh S. Myostatin: a therapeutic target for skeletal muscle wasting. Curr Opin Clin Nutr Metab Care. 2004;7(3):259–63.
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.
Manini TM, Vincent KR, Leeuwenburgh CL, et al. Myogenic and proteolytic mRNA expression following blood flow restricted exercise. Acta Physiol (Oxf). 2011;201(2):255–63.
Farooqui T. Iron-induced oxidative stress modulates olfactory learning and memory in honeybees. Behav Neurosci. 2008;122(2):433–47.
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.
Powers SK, Talbert EE, Adhihetty PJ. Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle. J Physiol. 2011;589(Pt 9):2129–38.
Jackson MJ. Reactive oxygen species and redox-regulation of skeletal muscle adaptations to exercise. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2285–91.
Simpson PJ, Lucchesi BR. Free radicals and myocardial ischemia and reperfusion injury. J Lab Clin Med. 1987;110(1):13–30.
Fulle S, Protasi F, Di Tano G, et al. The contribution of reactive oxygen species to sarcopenia and muscle ageing. Exp Gerontol. 2004;39(1):17–24.
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.
Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med. 2008;44(2):126–31.
Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann N Y Acad Sci. 2006;1067:425–35.
Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279(6):L1005–28.
Suzuki YJ, Ford GD. Redox regulation of signal transduction in cardiac and smooth muscle. J Mol Cell Cardiol. 1999;31(2):345–53.
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.
Kefaloyianni E, Gaitanaki C, Beis I. ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 2006;18(12):2238–51.
Tappia PS, Dent MR, Dhalla NS. Oxidative stress and redox regulation of phospholipase D in myocardial disease. Free Radic Biol Med. 2006;41(3):349–61.
Handayaningsih A, Iguchi G, Fukuoka H, et al. Reactive oxygen species play an essential role in IGF-I signaling and IGF-I-induced myocyte hypertrophy in C2C12 myocytes. Endocrinology. 2011;152(3):912–21.
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.
Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol. 2007;102(6):2379–88.
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.
Smith LW, Smith JD, Criswell DS. Involvement of nitric oxide synthase in skeletal muscle adaptation to chronic overload. J Appl Physiol. 2002;92(5):2005–11.
Sellman JE, DeRuisseau KC, Betters JL, et al. In vivo inhibition of nitric oxide synthase impairs upregulation of contractile protein mRNA in overloaded plantaris muscle. J Appl Physiol. 2006;100(1):258–65.
Anderson JE. A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells. Mol Biol Cell. 2000;11(5):1859–74.
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.
Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998;80(2):183–201.
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.
Locke M. Heat shock protein accumulation and heat shock transcription factor activation in rat skeletal muscle during compensatory hypertrophy. Acta Physiol (Oxf). 2008;192(3):403–11.
Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol. 2002;92(5):2177–86.
Paulsen G, Hanssen KE, Ronnestad BR, et al. Strength training elevates HSP27, HSP70 and alphaB-crystallin levels in musculi vastus lateralis and trapezius. Eur J Appl Physiol. 2012;112(5):1773–82.
Morton JP, Kayani AC, McArdle A, et al. The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med. 2009;39(8):643–62.
Haussinger D, Lang F, Gerok W. Regulation of cell function by the cellular hydration state. Am J Physiol. 1994;267(3 Pt 1):E343–55.
Haussinger D. The role of cellular hydration in the regulation of cell function. Biochem J. 1996;313(Pt 3):697–710.
Lang F, Busch GL, Ritter M, et al. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78(1):247–306.
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.
Lang F. Mechanisms and significance of cell volume regulation. J Am Coll Nutr. 2007;26(5 Suppl.):613S–23S.
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.
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.
Lambert IH, Hoffmann EK, Pedersen SF. Cell volume regulation: physiology and pathophysiology. Acta Physiol (Oxf). 2008;194(4):255–82.
Schliess F, Richter L, vom Dahl S, et al. Cell hydration and mTOR-dependent signalling. Acta Physiol (Oxf). 2006;187(1–2):223–9.
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.
Schliess F, Schreiber R, Haussinger 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.
Sjogaard G. Water and electrolyte fluxes during exercise and their relation to muscle fatigue. Acta Physiol Scand Suppl. 1986;556:129–36.
Sjogaard G, Adams RP, Saltin B. Water and ion shifts in skeletal muscle of humans with intense dynamic knee extension. Am J Physiol. 1985;248(2 Pt 2):R190–6.
Frigeri A, Nicchia GP, Verbavatz JM, et al. Expression of aquaporin-4 in fast-twitch fibers of mammalian skeletal muscle. J Clin Invest. 1998;102(4):695–703.
Kosek DJ, Kim JS, Petrella JK, et al. Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. J Appl Physiol. 2006;101(2):531–44.
Gundermann DM, Fry CS, Dickinson JM, et al. Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise. J Appl Physiol. 2012.
MacDougall JD, Ward GR, Sale DG, et al. Biochemical adaptation of human skeletal muscle to heavy resistance training and immobilization. J Appl Physiol. 1977;43(4):700–3.
Chan ST, Johnson AW, Moore MH, et al. Early weight gain and glycogen-obligated water during nutritional rehabilitation. Hum Nutr Clin Nutr. 1982;36(3):223–32.
Widegren U, Ryder JW, Zierath JR. Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contraction. Acta Physiol Scand. 2001;172(3):227–38.
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.
Mitchell CJ, Churchward-Venne TA, West DD, et al. Resistance exercise load does not determine training-mediated hypertrophic gains in young men. J Appl Physiol. 2012.
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.
Schoenfeld BJ. Does exercise-induced muscle damage play a role in skeletal muscle hypertrophy? J Strength Cond Res. 2012;26(5):1441–53.
This review was not funded by any outside organization. Brad Schoenfeld is the sole author of this work. There are no conflicts of interest present that are directly relevant to the content of this review.
About this article
Cite this article
Schoenfeld, B.J. Potential Mechanisms for a Role of Metabolic Stress in Hypertrophic Adaptations to Resistance Training. Sports Med 43, 179–194 (2013). https://doi.org/10.1007/s40279-013-0017-1
- Resistance Training
- Satellite Cell
- Resistance Exercise
- Phosphatidic Acid
- Muscle Hypertrophy