Mechanisms of Hypertrophy

Individuals might be training for the improvement of sports performance measures or for the benefits of their own health but in both situations, resistance training should play an important part in achieving these aims. 

Resistance training can result in increased functional strength, the stabilisation of joints and improved posture, increases in power output and increases in bone mineral density all of which, to some degree, rely on an increase in muscle mass, a process known as hypertrophy. While mechanisms other than hypertrophy also contribute to increases in strength, the muscle's ability to produce force clearly increases as it's cross-sectional area becomes greater (Ikai and Fukunaga,1968).

In order to be effective in programming activities that induce muscular hypertrophy, it’s key to first understand the mechanisms by which hypertrophy occurs. It’s been suggested that they fall broadly into 3 categories; mechanical tension, exercise induced muscular damage and metabolic stress.

This page gives a brief overview of these mechanisms for those that are keen exercisers or early career fitness professionals but also contains links to further, more detailed sources of information for those that are studying this area in greater depth. 

Once you've read this page you might like to read the accompanying page on neuromuscular factors

1. Mechanical Tension

Mechanical tension has been suggested as the primary driver for training induced muscular hypertrophy and results from performing a movement that requires some form of muscular contraction. 

Increased mechanical resistance disturbs the structure of skeletal muscle, and causes signals to be sent to the muscle fibres and cells to repair themselves and become stronger by favouring synthesis instead of breakdown. A series of events then follow this signalling process with, for example, increased levels of growth hormone being released. The mechanosensors responsible for initiating the signalling process are sensitive to both magnitude and duration of loading which has implications for the optimisation of training protocols.

Although mechanical tension alone can result in hypertrophy, some training protocols that predominantly employ large amounts of mechanical tension have been shown to induce neural adaptations rather than hypertrophic ones i.e. the participants became stronger without necessarily developing more muscle fibres. While this situation may be desirable in some cases, it places a limit on the potential for development as strength is largely related to the cross-sectional area of the muscles.

See Fry et al (2004) for more on the role of loading on muscle adaptations

For more on the biology of hypertrophy including cellular and molecular mechanisms see Spiering, et al. (2008), Schiaffino et  al. (2020). 

2. Muscle Damage

Intense exercise, particularly if novel or at an unaccustomed intensity, can cause damage to skeletal muscle. Anyone that’s performed a vigorous exercise for the first time (e.g. ridden a horse, completed a hard plyometric session or a long run) will have experienced the sensation of Delayed Onset Muscle Soreness (DOMS). DOMS along with muscular stiffness, swelling and reduced force-producing capacity are all symptoms of excessive Exercise Induced Muscle Damage (EIMD) which can in turn affect the ability to train at a high level. It’s worth noting at this point though that DOMS is a complex phenomenon and while linked to EIMD and micro-trauma, it has also been linked to inflammation, enzyme efflux, connective tissue damage, muscle spasm and lactic acid accumulation.

For hypertrophy to occur however, EIMD does not have to be so severe that it’s accompanied by DOMS. Although levels of EIMD have been shown to be a key factor in optimising hypertrophy, research has shown that excessive EIMD can be detrimental to hypertrophy for a number of reasons.

EIMD is influenced by the type of muscular action that is being executed and although concentric and isometric exercise can cause EIMD, eccentric exercise will be most likely to cause EIMD.

With regular exposure to a particular activity or exercise the likelihood of muscular microtrauma (EIMD) and particularly the symptoms of more severe damage like DOMS, are decreased. This is known as the repeated bout effect and knowledge of its existence can be useful in supporting those new to exercise but also help us appreciate the need for appropriately periodised and progressive programmes for more experienced trainers.

See Schoenfeld (2012), Schoenfeld and Contreras (2013) and Damas et al (2018) for more on EIMD.

3. Metabolic Stress

While it's important to lift heavy weights (at least in relation to an individual’s capabilities) so that appropriate levels of mechanical tension and exercise-induced muscle damage are created, it's also important that the environment in which the muscle operates and recovers is optimised for muscle growth. A resistance training protocol that utilises moderate to high loads, moderate to high reps and short recovery periods will create an exercise-induced accumulation of metabolites such as lactate, inorganic phosphates and H+ and this is known as metabolic stress.

Hypertrophic adaptations from exercise-induced metabolic stress include mechanisms related to increased fibre recruitment, elevated systemic hormonal production, alterations in local myokines, heightened production of reactive oxygen species (ROS) and cellular swelling.

The process of metabolic stress is that which underpins Blood Flow Restriction (BFR) training and hypoxic resistance training, both of which seek to create heightened levels of ischemia in the working muscle as they contract. For more on BFR see Loenneke et al (2014) and for more on hypoxic training see Scott et al (2015).

See Schoenfeld (2013) for more on metabolic stress

Further Reading

If you only read one paper #1: A concise read

Schoenfeld, B. J. (2010). The mechanisms of muscle hypertrophy and their application to resistance training. The Journal of Strength & Conditioning Research, 24(10), 2857-2872.   [www]

Recent Reviews

Egan, B., & Sharples, A. P. (2023). Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiological Reviews. 

Roberts, M. D., McCarthy, J. J., Hornberger, T. A., Phillips, S. M., Mackey, A. L., Nader, G. A., ... & Esser, K. A. (2023). Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions. Physiological Reviews. 

Wackerhage, H., Schoenfeld, B. J., Hamilton, D. L., Lehti, M., & Hulmi, J. J. (2019). Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise. Journal of applied physiology, 126(1), 30-43. 

Lim, C., Nunes, E. A., Currier, B. S., Mcleod, J. C., Thomas, A. C., & Phillips, S. M. (2022). An Evidence-based Narrative Review of Mechanisms of Resistance Exercise-induced Human Skeletal Muscle Hypertrophy. Medicine & Science in Sports & Exercise, 10-1249.

If you want to buy a book

Timeline of major studies that paved the way to current understanding of how physical activity controls muscle size 

Image from: Attwaters, M., & Hughes, S. M. (2022). Cellular and molecular pathways controlling muscle size in response to exercise. The FEBS journal, 289(6), 1428-1456. 

References/Extended Reading List

Attwaters, M., & Hughes, S. M. (2022). Cellular and molecular pathways controlling muscle size in response to exercise. The FEBS journal, 289(6), 1428-1456. 

Balshaw, T. G., Massey, G. J., Maden-Wilkinson, T. M., Morales-Artacho, A. J., McKeown, A., Appleby, C. L., & Folland, J. P. (2017). Changes in agonist neural drive, hypertrophy and pre-training strength all contribute to the individual strength gains after resistance training. European journal of applied physiology, 117(4), 631-640. 

Beardsley, C. (n.d.) Hypertrophy Mechanisms

Bersiner, K., Park, S-Y, Schaaf, K., Yang, W-H, Theis, C., Jacko, D., & Gehlert, S.  (2023) Resistance exercise: a mighty tool that adapts, destroys, rebuilds and modulates the molecular and structural environment of skeletal muscle. Phys Act Nutr 27(2):078-095. 

Brentano, M. A., & Martins Kruel, L. F. (2011). A review on strength exercise-induced muscle damage: applications, adaptation mechanisms and limitations. J Sports Med Phys Fitness, 51(1), 1-10. [abstract]

Buckner, S. L., Jessee, M. B., Mouser, J. G., Dankel, S. J., Mattocks, K. T., Bell, Z. W., ... & Loenneke, J. P. (2019). The Basics of Training for Muscle Size and Strength: A Brief Review on the Theory. Medicine and Science in Sports and Exercise. 

Burke, R., Piñero, A., Coleman, M., Mohan, A., Sapuppo, M., Augustin, F., ... & Schoenfeld, B. J. (2023). The Effects of Creatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy: A Systematic Review with Meta-Analysis. Nutrients, 15(9), 2116. 

Bush-Joseph, C. A. (2012). Muscle Soreness and Delayed-Onset Muscle Soreness. Clin Sports Med, 31, 255-262.[abstract]

Carvalho, L. H. F., Junior, R. M., Barreira, J., Schoenfeld, B. J., Orazem, J., & Barroso, R. (2022). Muscle hypertrophy and strength gains after resistance training with different volume matched loads: a systematic review and meta-analysis. Applied Physiology, Nutrition, and Metabolism, 47(4) 

Chapman, D., Newton, M., Sacco, P., & Nosaka, K. (2006). Greater muscle damage induced by fast versus slow velocity eccentric exercise. International Journal of Sports Medicine, 27(08), 591-598. 

Clarkson, P. M., & Hubal, M. J. (2002). Exercise-induced muscle damage in humans. American Journal of Physical Medicine & Rehabilitation, 81(11), S52-S69.[abstract]

Damas, F., Libardi, C. A., & Ugrinowitsch, C. (2018). The development of skeletal muscle hypertrophy through resistance training: the role of muscle damage and muscle protein synthesis. European journal of applied physiology, 118(3), 485-500. 

Dankel, S. J., Mattocks, K. T., Jessee, M. B., Buckner, S. L., Mouser, J. G., Counts, B. R., ... & Loenneke, J. P. (2017). Frequency: the overlooked resistance training variable for inducing muscle hypertrophy?. Sports Medicine, 47(5), 799-805.  

Davies, T., Halaki, M., Orr, R., Mitchell, L., Helms, E., Clarke, J., Hackett, D. (2021) Effect of Set-Structure on Upper-Body Muscular Hypertrophy and Performance in Recreationally-Trained Male and Female, Journal of Strength and Conditioning Research doi: 0.1519/JSC.00000000000039

de Salles, B. F., Simao, R., Miranda, F., da Silva Novaes, J., Lemos, A., & Willardson, J. M. (2009). Rest interval between sets in strength training. Sports Medicine, 39(9), 765-777. 

Egan, B., & Sharples, A. P. (2023). Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiological Reviews. 

Feriche, B., García-Ramos, A., Morales-Artacho, A. J., & Padial, P. (2017). Resistance Training Using Different Hypoxic Training Strategies: a Basis for Hypertrophy and Muscle Power Development. Sports Medicine-Open, 3(1), 12. 

Folland, J. P., & Williams, A. G. (2007). Morphological and neurological contributions to increased strength. Sports Medicine, 37(2), 145-168. 

Fry, A. C. (2004). The role of resistance exercise intensity on muscle fibre adaptations. Sports Medicine, 34(10), 663-679. 

Grgic, J., Schoenfeld, B. J., Orazem, J. & Sabol, F. (2021) Effects of resistance training performed to repetition failure or non-failure on muscular strength and hypertrophy: a systematic review and meta-analysis Journal of Sport and Health Science 

Haun, C. T., Vann, C. G., Roberts, B. M., Vigotsky, A. D., Schoenfeld, B. J., & Roberts, M. D. (2019). A critical evaluation of the biological construct skeletal muscle hypertrophy: size matters but so does the measurement. Frontiers in Physiology, 10. 

Hody, S., Croisier, J. L., Bury, T., Rogister, B., & Leprince, P. (2019). Eccentric muscle contractions: risks and benefits. Frontiers in Physiology, 10, 536.   

Hornberger, T. A. (2011). Mechanotransduction and the regulation of mTORC1 signaling in skeletal muscle. The international journal of biochemistry & cell biology, 43(9), 1267-1276. 

Howe, L. P., Read, P., & Waldron, M. (2017). Muscle hypertrophy: A narrative review on training principles for increasing muscle mass. Strength & Conditioning Journal, 39(5), 72-81. doi: 10.1519/SSC.0000000000000330 

Ikai, M., & Fukunaga, T. (1968). Calculation of muscle strength per unit cross-sectional area of human muscle by means of ultrasonic measurement. Internationale Zeitschrift für Angewandte Physiologie Einschliesslich Arbeitsphysiologie, 26(1), 26-32. 

Kataoka, R., Hammert, W.B., Yamada, Y. et al. (2023) The Plateau in Muscle Growth with Resistance Training: An Exploration of Possible Mechanisms. Sports Medicine 

Kraemer, W. J., & Ratamess, N. A. (2005). Hormonal responses and adaptations to resistance exercise and training. Sports Medicine, 35(4), 339-361.  

Krzysztofik, M., Wilk, M., Wojdała, G., & Gołaś, A. (2019). Maximizing muscle hypertrophy: a systematic review of advanced resistance training techniques and methods. International journal of environmental research and public health, 16(24), 4897. 

Lewis, P. B., Ruby, D., & Bush-Joseph, C. A. (2012). Muscle soreness and delayed-onset muscle soreness. Clinics in Sports Medicine, 31(2), 255-262. [abstract]

Lim, C., Nunes, E. A., Currier, B. S., Mcleod, J. C., Thomas, A. C., & Phillips, S. M. (2022). An Evidence-based Narrative Review of Mechanisms of Resistance Exercise-induced Human Skeletal Muscle Hypertrophy. Medicine & Science in Sports & Exercise, 10-1249. 

Loenneke, J. P., Wilson, G. J., & Wilson, J. M. (2010). A mechanistic approach to blood flow occlusion. International Journal of Sports Medicine, 31(01), 1-4. 

Loenneke, J. P., Buckner, S. L., Dankel, S. J., & Abe, T. (2019). Exercise-induced changes in muscle size do not contribute to exercise-induced changes in muscle strength. Sports Medicine, 1-5. [See Taber et al below for counterpoint]

Loenneke, J. P., Dankel, S. J., Bell, Z. W., Buckner, S. L., Mattocks, K. T., Jessee, M. B., & Abe, T. (2019). Is muscle growth a mechanism for increasing strength?. Medical hypotheses, 125, 51-56. 

Lopez, P., Radaelli, R., Taaffe, D. R., Newton, R. U., Galvão, D. A., Trajano, G. S., Teodoro, J., Kraemer, W. J., Häkkinen, K., & Pinto, R. S. (2020). Resistance Training Load Effects on Muscle Hypertrophy and Strength Gain: Systematic Review and Network Meta-analysis. Medicine and science in sports and exercise, 

McHugh, M. P. (2003). Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scandinavian Journal of Medicine & Science in Sports, 13(2), 88-97. 

McKendry, J., Pérez‐López, A., McLeod, M., Luo, D., Dent, J. R., Smeuninx, B., ... & Breen, L. (2016). Short inter‐set rest blunts resistance exercise‐induced increases in myofibrillar protein synthesis and intracellular signalling in young males. Experimental physiology, 101(7), 866-882. 

Morton, R. W., Colenso-Semple, L., & Phillips, S. M. (2019). Training for Strength and Hypertrophy: An Evidence-based Approach. Current Opinion in Physiology. 

Morton, R. W., Murphy, K. T., McKellar, S. R., Schoenfeld, B. J., Henselmans, M., Helms, E., ... & Phillips, S. M. (2018). A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. British journal of sports medicine, 52(6), 376-384. 

Morton, R. W., Oikawa, S. Y., Wavell, C. G., Mazara, N., McGlory, C., Quadrilatero, J., ... & Phillips, S. M. (2016). Neither load nor systemic hormones determine resistance training-mediated hypertrophy or strength gains in resistance-trained young men. Journal of applied physiology, 121(1), 129-138. 

Muscle and Sport Science (M.A.S.S.) (2012) The role of muscle damage in hypertrophy 

Nosaka, K., Lavender, A., Newton, M., & Sacco, P. (2003). Muscle damage in resistance training: Is muscle damage necessary for strength gain and muscle hypertrophy? International Journal of Sport and Health Science, 1(1), 1-8. 

Nunes, E. A., Colenso‐Semple, L., McKellar, S. R., Yau, T., Ali, M. U., Fitzpatrick‐Lewis, D., ... & Phillips, S. M. (2022). Systematic review and meta‐analysis of protein intake to support muscle mass and function in healthy adults. Journal of cachexia, sarcopenia and muscle, 13(2), 795-810. 

Phillips, S. M. (2014). A brief review of critical processes in exercise-induced muscular hypertrophy. Sports Medicine, 44(1), 71-77. 

Roberts, M. D., Haun, C. T., Vann, C. G., Osburn, S. C., & Young, K. C. (2020). Sarcoplasmic hypertrophy in skeletal muscle: A scientific “unicorn” or resistance training adaptation?. Frontiers in Physiology, 11, 816. 

Roberts, M. D., McCarthy, J. J., Hornberger, T. A., Phillips, S. M., Mackey, A. L., Nader, G. A., ... & Esser, K. A. (2023). Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions. Physiological Reviews. 

Sartori, R., Romanello, V. & Sandri, M.  (2021) Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun 12, 330 

Scarpelli, M. C., Nóbrega, S. R., Santanielo, N., Alvarez, I. F., Otoboni, G. B., Ugrinowitsch, C., & Libardi, C. A. (2020). Muscle hypertrophy response is affected by previous resistance training volume in trained individuals. J Strength Cond Res, 27. 

Schiaffino, S., Reggiani, C., Akimoto, T., & Blaauw, B. (2020). Molecular Mechanisms of Skeletal Muscle Hypertrophy. Journal of Neuromuscular Diseases, 8(2), 169-183. 

Schoenfeld, B., & Grgic, J. (2017). Evidence-Based Guidelines for Resistance Training Volume to Maximize Muscle Hypertrophy. Strength & Conditioning Journal.doi: 10.1519/SSC.0000000000000363

Schoenfeld, B. J., & Grgic, J. (2019). Does training to failure maximize muscle hypertrophy?. Strength & Conditioning Journal, 41(5), 108-113. 

Schoenfeld, B. J. (2013). Potential mechanisms for a role of metabolic stress in hypertrophic adaptations to resistance training. Sports Medicine, 43(3), 179-194.

Schoenfeld, B. J. (2012). Does exercise-induced muscle damage play a role in skeletal muscle hypertrophy? The Journal of Strength & Conditioning Research, 26(5), 1441-1453. 

Schoenfeld, B. J., & Contreras, B. (2013). Is postexercise muscle soreness a valid indicator of muscular adaptations?. Strength & Conditioning Journal, 35(5), 16-21. doi: 10.1519/SSC.0b013e3182a61820

Schoenfeld, B. J., Grgic, J., Ogborn, D., & Krieger, J. W. (2017). Strength and hypertrophy adaptations between low-vs. high-load resistance training: a systematic review and meta-analysis. The Journal of Strength & Conditioning Research, 31(12), 3508-3523. 

Schroeder, E. T., Villanueva, M., West, D. D., & Phillips, S. M. (2013). Are acute post-resistance exercise increases in testosterone, growth hormone, and IGF-1 necessary to stimulate skeletal muscle anabolism and hypertrophy?. Medicine and science in sports and exercise, 45(11), 2044–2051. 

Scott, B. R., Slattery, K. M., & Dascombe, B. J. (2015). Intermittent hypoxic resistance training: Is metabolic stress the key moderator?. Medical Hypotheses, 84(2), 145-149. 

Shaw, B. S., Shaw, I., & Brown, G. A. (2015). Resistance exercise is medicine: Strength training in health promotion and rehabilitation. International Journal of Therapy and Rehabilitation, 22(8), 385-389. 

Smilios, I., Pilianidis, T., Karamouzis, M., & Tokmakidis, S. P. (2003). Hormonal responses after various resistance exercise protocols. Medicine and Science in Sports and Exercise, 35(4), 644. 

Spiering, B. A., Kraemer, W. J., Anderson, J. M., Armstrong, L. E., Nindl, B. C., Volek, J. S., & Maresh, C. M. (2008). Resistance exercise biology: Manipulation of Resistance Exercise Programme Variables Determines the Responses of Cellular and Molecular Signalling Pathways. Sports Medicine, 38(7), 527-540. 

Steele, J., Fisher, J. P., Smith, D., Schoenfeld, B., Yang, Y., & Nakagawa, S. (2023). Meta-analysis of variation in sport and exercise science: examples of application within resistance training research. Journal of Sports Sciences, 1-18.  

Stokes, T., Timmons, J. A., Crossland, H., Tripp, T. R., Murphy, K., McGlory, C., ... & Phillips, S. M. (2020). Molecular transducers of human skeletal muscle remodeling under different loading states. Cell Reports, 32(5). 

Taber, C. B., Vigotsky, A., Nuckols, G., & Haun, C. T. (2019). Exercise-induced myofibrillar hypertrophy is a contributory cause of gains in muscle strength. Sports Medicine, 1-5. [see Loenneke et al above for counterpoint and audio debate in recommended resources]

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Wernbom, M., Augustsson, J., & Thomeé, R. (2007). The influence of frequency, intensity, volume and mode of strength training on whole muscle cross-sectional area in humans. Sports Medicine, 37(3), 225-264.   

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