Angiotensin‐Converting Enzyme Genotype Affects the Response of Human Skeletal Muscle to Functional Overload
Open accessAbstract
The response to strength training varies widely between individuals and is considerably influenced by genetic variables, which until now, have remained unidentified. The deletion (D), rather than the insertion (I), variant of the human angiotensin‐converting enzyme (ACE) genotype is an important factor in the hypertrophic response of cardiac muscle to exercise and could also be involved in skeletal muscle hypertrophy – an important factor in the response to functional overload. Subjects were 33 healthy male volunteers with no experience of strength training. We examined the effect of ACE genotype upon changes in strength of quadriceps muscles in response to 9 weeks of specific strength training (isometric or dynamic). There was a significant interaction between ACE genotype and isometric training with greater strength gains shown by subjects with the D allele (mean ± S.E.M.: II, 9.0 ± 1.7%; ID, 17.6 ± 2.2%; DD, 14.9 ± 1.3%, ANOVA, P 0.05). A consistent genotype and training interaction (ID DD II) was observed across all of the strength measures, and both types of training. ACE genotype is the first genetic factor to be identified in the response of skeletal muscle to strength training. The association of the ACE I/D polymorphism with the responses of cardiac and skeletal muscle to functional overload indicates that they may share a common mechanism. These findings suggest a novel mechanism, involving the renin‐angiotensin system, in the response of skeletal muscle to functional overload and may have implications for the management of conditions such as muscle wasting disorders, prolonged bed rest, ageing and rehabilitation, where muscle weakness may limit function.
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Erskine et al. reported average isometric strength gains approximately 2-fold greater than those found in the present study (31% vs. 11.5-18.2%).
“Erskine et al. (30), reported average isometric strength gains ~2-fold greater than we have found [31% vs. 11.5–18.2% (31, 32)]”
From What makes long-term resistance-trained individuals so strong? A comparison of skeletal muscle morphology, architecture, and joint mechanics (2020) · cites this paper as [32]
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“modulated by the renin–angiotensin system (Folland et al., 2000; Onder et al., 2006).”
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“The D allele, meanwhile, has been associated with sprinting (Myerson et al. 1999) and with training-related gains in strength (Folland et al. 2000).”
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“Folland et al. (2000) studied the influence of the ACE I/D polymorphism on quadriceps strength response to strength training.”
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Self-citationThe Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2003 Update
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“05 (32) 83 PM women Specific muscle strength of adductor pollicis 0.”
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“Studies concerning the eVect of ACE genotype on skeletal muscle strength and mass in response to strength training have yielded inconsistent results (Folland et al. 2000; Pescatello et al. 2006; Thomis et al. 2004; Williams et al. 2005).”
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“2% (31, 32)], with almost identical training regimes and the same number of training sessions, and this discrepancy likely explains the large increase in specific tension they have reported.”
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“Accordingly, greater training-related increases in quadriceps muscle strength (Folland et al., 2000; Giaccaglia et al., 2008), peak elbow flexor muscle strength and biceps muscle cross-sectional area (Pescatello et al., 2006) have been associated with the D allele.”
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“Based on previous studies (Folland et al. 2000; Pescatello et al. 2006), Dallele of the ACE gene would not be associated with baseline measures of skeletal muscle strength, and this hypothesis was partially supported.”
ResultRelationship between angiotensin-converting enzyme ID polymorphism and VO2max of Chinese males
Zhao, B., Moochhala, S., Tham, S.-Y., et al. (2003) · Life Sciences · doi:10.1016/s0024-3205(03)00608-8 · Cited by 62 · see citing works
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Buford, T. W., Manini, T. M., Hsu, F., Cesari, M., Anton, S. D., Nayfield, S., Stafford, R. S., Church, T. S., Pahor, M., & Carter, C. S. (2012) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2012.04045.x · Cited by 59 · see citing works
“Moderate-intensity exercise was promoted and assessed using the Borg scale,(29) a numerical scale indicating effort from minimal(6) to maximal.(20) Participants were asked to walk at a target intensity of 13 (somewhat hard) and perform strength training at an intensity of 15 to 16 (hard).”
MethodResultMcCauley, T., Mastana, S. S., Hossack, J., MacDonald, M., & Folland, J. P. (2008) · Experimental Physiology · doi:10.1113/expphysiol.2008.043075 · Cited by 58 · see citing works
“Several investigations have found no association of ACE genotype with isometric and dynamic strength (Folland et al. 2000; Thomis et al. 2004; Woods et al. 2001; Pescatello et al. 2006), although the D allele has been associated with greater isometric strength in chronic obstructive pulmonary…”
BackgroundResultInfluentialSelf-citationAhmetov, I. I., Gavrilov, D. N., Astratenkova, I. V., Druzhevskaya, A. M., Malinin, A. V., Romanova, E. E., & Rogozkin, V. A. (2012) · The Journal of Physiological Sciences · doi:10.1007/s12576-012-0233-8 · Cited by 57 · see citing works
“Accordingly, greater training-related increases in quadriceps muscle strength [7, 8], peak elbow flexor muscle strength and biceps muscle cross-sectional area [9] have been associated with the D allele.”
Physical activity and angiotensin‐converting enzyme gene polymorphism in mild hypertensives
Winnicki, M., Accurso, V., Hoffmann, M., et al. (2003) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.20434 · Cited by 57 · see citing works
“, 1997], greater strength gain in muscles in response to physical training [Folland et al., 2000] and chaotic glucose oxygenation in muscles [Townsend and DiPette, 1993] delivering vast amount of energy in a very short period, one of the key features necessary for successful heavy-resistance exercise.”
BackgroundSports genomics: Current state of knowledge and future directions
Ahmetov, I. I., & Fedotovskaya, O. N. (2012) · Cellular and Molecular Exercise Physiology · doi:10.7457/cmep.v1i1.e1 · Cited by 57 · see citing works
“Accordingly, greater training-related increases in quadriceps muscle strength (Giaccaglia et al., 2008; Folland et al., 2000), peak elbow flexor muscle strength and biceps muscle cross-sectional area (Pescatello et al., 2006), and changes in left ventricular growth (Montgomery et al., 1997) have…”
BackgroundOptimizing the Benefits of Exercise on Physical Function in Older Adults
Buford, T., Anton, S. D., Clark, D. J., Higgins, T. J., & Cooke, M. B. (2013) · PM & R : the journal of injury, function, and rehabilitation · doi:10.1016/j.pmrj.2013.11.009 · Cited by 56 · see citing works
“These findings add to an extensive literature from genetic studies in humans, which demonstrated an important interaction between the reninangiotensin system and exercise training [59-64].”
ACE I/D and ACTN3 R/X polymorphisms and muscle function and muscularity of older Caucasian men
McCauley, T., Mastana, S. S., & Folland, J. P. (2010) · European Journal of Applied Physiology · doi:10.1007/s00421-009-1340-y · Cited by 57 · see citing works
“Several investigations have found no association of ACE genotype with isometric and dynamic strength in young and older adults (Folland et al. 2000; Mc Cauley et al. 2009; Pescatello et al. 2006; Woods et al. 2001b).”
BackgroundResultSelf-citationVerbrugge, S. A. J., Schönfelder, M., Becker, L., Yaghoob Nezhad, F., Hrabě de Angelis, M., & Wackerhage, H. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00553 · Cited by 56 · see citing works
“In humans, the angiotensin-converting enzyme ACE D deletion allele was associated with greater strength gain after resistance training but the study only involved 33 subjects (Folland et al., 2000).”
BackgroundHand, B. D., Kostek, M. C., Ferrell, R. E., Delmonico, M. J., Douglass, L. W., Roth, S. M., Hagberg, J. M., & Hurley, B. F. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00420.2007 · Cited by 53 · see citing works
“However, there have been few candidate genes identified that influence muscle responses to ST (2, 10, 20, 24, 39), and there are no reports, that we are aware of, on the influence of candidate genes that are linked in a common physiological pathway.”
BackgroundGenes, Athlete Status and Training – An Overview
Ahmetov, I. I., & Rogozkin, V. A. (2009) · Medicine and sport science/Medicine and sport · doi:10.1159/000235696 · Cited by 54 · see citing works
de Almeida, J. A., Mota, M. R., Oliveira, R. J., Terra, D. F., Pardono, E., Dutra, M. T., & da Silva, F. M. (2013) · International Journal of General Medicine · doi:10.2147/ijgm.s40628 · Cited by 51 · see citing works
“The I/D polymorphism of the ACE gene might be related to different effects of resistance exercise related to health, such as strength gains, muscle hypertrophy,(38,39) and BP response to exercise.(40) In addition, it appears that the DD genotype of the ACE gene is associated with a higher incidence of hypertension.”
Genomics of Elite Sporting Performance
Wang, G., Padmanabhan, S., Wolfarth, B., Fuku, N., Lucía, A., Ahmetov, I. I., Cięszczyk, P., Collins, M., Eynon, N., Klissouras, V., et al. (2013) · Advances in genetics · doi:10.1016/b978-0-12-407703-4.00004-9 · Cited by 52 · see citing works
Low-Grade Systemic Inflammation and the Response to Exercise Training in Patients With Advanced COPD
Spruit, M. A., Gosselink, R., Troosters, T., Kasran, A., van Vliet, M., & Decramer, M. (2005) · CHEST Journal · doi:10.1378/chest.128.5.3183 · Cited by 47 · see citing works
Keogh, J., Hume, P. A., Pearson, S. N., & Mellow, P. (2009) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e3181b8d67a · Cited by 48 · see citing works
“The between-group differences in muscle mass and upper-body muscular girths per unit height may therefore reflect differences in a) resistance training/powerlifting experience; b) training practices; c) the use of performance-enhancing agents such as drugs; and d) a genetic profile that provided a greater pretraining…”
BackgroundACEandACTN3Genotypes in Older Women: Muscular Phenotypes
Lima, R. M., Leite, T. K. M., Pereira, R. W., Rabelo, H. T., Roth, S. M., & Oliveira, R. (2010) · International Journal of Sports Medicine · doi:10.1055/s-0030-1267229 · Cited by 48 · see citing works
Bruton, A. (2002) · Physiotherapy · doi:10.1016/s0031-9406(05)61265-5 · Cited by 48 · see citing works
Dionísio, T. J., Thiengo, C. R., Brozoski, D., Dionísio, E. J., Talamoni, G. A., Silva, R. B., Garlet, G. P., Santos, C. F., & Amaral, S. L. (2017) · Applied Physiology Nutrition and Metabolism · doi:10.1139/apnm-2016-0608 · Cited by 44 · see citing works
Genetic score of power‐speed and endurance track and field athletes
Ben‐Zaken, S., Meckel, Y., Nemet, D., et al. (2013) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/sms.12141 · Cited by 44 · see citing works
“Conversely, an excess of the D allele has been reported among elite power-oriented athletes (Myerson et al., 1999) in a mechanism that is most likely mediated through differences in skeletal muscle strength gain (Folland et al., 2000).”
BackgroundGenetic aspects of skeletal muscle strength and mass with relevance to sarcopenia
Roth, S. M. (2012) · BoneKEy Reports · doi:10.1038/bonekey.2012.58 · Cited by 41 · see citing works
Westerkamp, C. M., & Gordon, S. E. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00730.2004 · Cited by 41 · see citing works
“Also, the ACE deletion allele genotype (conferring greater ACE activity) is associated with a greater hypertrophic response to functional overload in human skeletal muscle (17).”
BackgroundValidated treatments and therapeutics prospectives regarding pharmacological products for sarcopenia
Onder, G., Vedova, C. D., & Landi, F. (2009) · The journal of nutrition health & aging · doi:10.1007/s12603-009-0209-4 · Cited by 39 · see citing works
“Overall, statin users performed modestly better than nonusers for timed chair stands (-0.5 seconds; P=.04).”
InfluentialThe use of molecular genetic methods for prognosis of aerobic and anaerobic performance in athletes
Ahmetov, I. I., Викторович, П. Д., Astratenkova, I. V., et al. (2008) · Human Physiology · doi:10.1134/s0362119708030110 · Cited by 39 · see citing works
“ACE Production of angiotensin II, activation of aldosterone synthesis, bradykinin decomposition I : optimal vascular tone, predominance of slow muscle fibers, predisposition for development of aerobic and anaerobic endurance [2, 3, 5, 8] D : increased vascular tone; predominance of fast muscle fibers; predisposition f…”
C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women
Roth, S. M., Metter, E. J., Lee, M. R., Hurley, B. F., & Ferrell, R. E. (2003) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00516.2003 · Cited by 39 · see citing works
“Polymorphisms in CNTF (28), myostatin (18), type I collagen- 1 (40), angiotensin converting enzyme (8, 45), vitamin D receptor (11), and insulin-like growth factor 1 (33) have been tentatively identified to date as being associated with muscle-related phenotypes.”
BackgroundThe AGT Gene M235T Polymorphism and Response of Power-Related Variables to Aerobic Training.
Zarębska, A., Jastrzębski, Z., Moska, W., Leońska‐Duniec, A., Kaczmarczyk, M., Sawczuk, M., Agnieszka, M.-S., Żmijewski, P., Ficek, K., Grzegorz, T., et al. (2016) · Europe PMC (PubMed Central) · Cited by 41 · see citing works
Exercise And Skeletal Muscle Gene Expression
Cameron‐Smith, D. (2002) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2002.03621.x · Cited by 37 · see citing works
Shenoy, S., Tandon, S., Sandhu, J. S., et al. (2010) · Asian Journal of Sports Medicine · doi:10.5812/asjsm.34855 · Cited by 36 · see citing works
“Folland et al.([13]) conducted a study on 33 healthy males involving 9 weeks of quadriceps strength training to examine the effect of ACE polymorphism on physical performance and finding greater strength gains in subjects with D- allele.”
BackgroundRelationship between ace genotype and short duration aerobic performance development
Cerit, M., Çolakoğlu, M., Erdoğan, M., et al. (2006) · European Journal of Applied Physiology · doi:10.1007/s00421-006-0286-6 · Cited by 35 · see citing works
“ACE DD genotype may be associated with a greater skeletal muscle strength gain in response to training (Colakoglu et al. 2005; Folland et al. 2000; Hopkinson et al. 2004) and a higher anaerobic capacity (Woods et al. 2001).”
BackgroundAssociation of Genetic Factors With Selected Measures of Physical Performance
Thompson, W. R., & Binder‐Macleod, S. A. (2006) · Physical Therapy · doi:10.1093/ptj/86.4.585 · Cited by 35 · see citing works
ACE Genotype May Have an Effect on Single versus Multiple Set Preferences in Strength Training
Çolakoğlu, M., Çam, F. S., Kayıtken, B., Çetinöz, F., Colakoglu, S., Turkmen, M., & Sayin, M. (2005) · European Journal of Applied Physiology · doi:10.1007/s00421-005-1335-2 · Cited by 34 · see citing works
“Indeed, data from Folland et al. (2000) support this notion.”
BackgroundHigher Frequency of the ACTN3 R Allele + ACE DD Genotype in Japanese Elite Wrestlers
Kikuchi, N., Min, S.-K., Ueda, D., Igawa, S., & Nakazato, K. (2012) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e318273679d · Cited by 34 · see citing works
“(8) reported that a greater increase in muscle strength was observed in ACE ID + DD genotype athletes who underwent a 9-week isometric strength training program.”
BackgroundWagner, H., Thaller, S., Dahse, R., & Šust, M. (2006) · European Journal of Applied Physiology · doi:10.1007/s00421-006-0293-7 · Cited by 34 · see citing works
“was reported with greater strength gains shown by subjects with a D allele (Folland et al. 2000).”
BackgroundEffect of angiotensin‐converting enzyme inhibition on cardiovascular adaptation to exercise training
Sjúrðarson, T., Bejder, J., Andersen, A. B., Bonne, T. C., Kyhl, K., Róin, T., Patursson, P., Gregersen, N. O., Skoradal, M., Schliemann, M., et al. (2022) · Physiological Reports · doi:10.14814/phy2.15382 · Cited by 31 · see citing works
“…human studies have shown that individuals with an innate disposition towards higher levels of serum ACE and thus higher production of angiotensin II, demonstrate greater strength gains in response to exercise training (Folland et al., 2000; Giaccaglia et al., 2008; Puthucheary et al., 2011).”
BackgroundGene polymorphisms and elite athletic performance.
Calò, M. C., & Vona, G. (2008) · PubMed · Cited by 30 · see citing works
Wang, P., Fedoruk, M., & Rupert, J. L. (2008) · Sports Medicine · doi:10.2165/00007256-200838120-00008 · Cited by 30 · see citing works
Coelho, V. A., Probst, V. S., Nogari, B. M., Teixeira, D. D. C., Felcar, J. M., dos Santos, D. C., Gomes, M. V., Andraus, R. A. C., & Fernandes, K. B. P. (2016) · Journal of Physical Therapy Science · doi:10.1589/jpts.28.547 · Cited by 28 · see citing works
[Using molecular genetic methods for prognosis of aerobic and anaerobic performance in athletes].
Akhmetov, I. I., Викторович, П. Д., Astratenkova, I. V., et al. (2008) · PubMed · Cited by 30 · see citing works
Çam, F. S., Çolakoğlu, M., Şekuri, C., et al. (2005) · Canadian Journal of Applied Physiology · doi:10.1139/h05-106 · Cited by 29 · see citing works
“, 2003) and greater strength gain in the quadriceps muscle in response to training (Folland et al., 2000).”
BackgroundUnderstanding Personalized Training Responses: Can Genetic Assessment Help?
Pickering, C., & Kiely, J. (2017) · The Open Sports Sciences Journal · doi:10.2174/1875399x01710010191 · Cited by 29 · see citing works
“[PMID: 17557065] [70] Folland J, Leach B, Little T, et al.”
Is there a gender difference between ACE gene and race distance?
Min, S.-K., Takahashi, K., Ishigami, H., Hiranuma, K., Mizuno, M., Ishii, T., Kim, C., & Nakazato, K. (2009) · Applied Physiology Nutrition and Metabolism · doi:10.1139/h09-097 · Cited by 28 · see citing works
“The ACE D allele has been associated with training-related gains in strength (Fatini et al. 2000; Folland et al. 2000; Jones and Woods 2003).”
BackgroundAngiotensin-Converting Enzyme, Renin-Angiotensin System and Human Performance
Woods, D. R. (2009) · Medicine and sport science/Medicine and sport · doi:10.1159/000235697 · Cited by 27 · see citing works
Mägi, A., Unt, E., Prans, E., Raus, L., Eha, J., Veraksitš, A., Kingo, K., & Kõks, S. (2016) · PubMed Central · Cited by 25 · see citing works
The association between D allele of the ACE gene and power performance in Polish elite athletes
Еider, J., Cięszczyk, P., Ficek, K., et al. (2013) · Science & Sports · doi:10.1016/j.scispo.2012.11.005 · Cited by 24 · see citing works
Mapping Robust Genetic Variants Associated with Exercise Responses
Alvarez‐Romero, J., Voisin, S. A. C., Eynon, N., & Hiam, D. (2020) · International Journal of Sports Medicine · doi:10.1055/a-1198-5496 · Cited by 23 · see citing works
Boraíta, A., de la Rosa, A., Heras, M. E., et al. (2010) · Revista Española de Cardiología (English Edition) · doi:10.1016/s1885-5857(10)70166-3 · Cited by 20 · see citing works
Wagle, J. P., Carroll, K. M., Cunanan, A. J., Wetmore, A. B., Taber, C. B., DeWeese, B. H., Sato, K., Stuart, C. A., & Stone, M. H. (2018) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000002809 · Cited by 18 · see citing works
“Although valuable, these investigations often focused on the untrained (3,9,10) or elderly (19).”
BackgroundResultWoods, D. R., Sanders, J., Jones, A., Hawe, E., Gohlke, P., Humphries, S. E., Payne, J., & Montgomery, H. (2004) · European Journal of Applied Physiology · doi:10.1007/s00421-003-0993-1 · Cited by 19 · see citing works
Self-citationCorrà, U., Mezzani, A., Giannuzzi, P., & Tavazzi, L. (2003) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2003.10.002 · Cited by 19 · see citing works
The Role of Genetic Variation in Muscle Strength
Kostek, M. C., Hubal, M. J., & Pescatello, L. S. (2010) · American Journal of Lifestyle Medicine · doi:10.1177/1559827610387251 · Cited by 20 · see citing works
“However, previously untrained men with the ACE D allele gained more isometric leg strength following RT when compared with those with the ACE II genotype.(48) Depending on the type of exercise intervention (RT or general exercise), either the I or D allele of the ACE I/D polymorphism may influence muscle strength.”
MethodBoraíta, A., de la Rosa, A., Heras, M. E., et al. (2010) · Revista Española de Cardiología · doi:10.1016/s0300-8932(10)70184-6 · Cited by 17 · see citing works
- Authors
- Folland, J., Leach, B., Little, T., Hawker, K., Myerson, S., Montgomery, H., & Jones, D.
- Affiliations
- University College London (GB)
- Corresponding author
- Folland, Jonathan
- Venue
- Experimental Physiology
- Publisher
- Wiley
- Published
- 2000-09
- Volume
- 85
- Issue
- 5
- Pages
- 575-579
- ISSN
- 0958-0670 (ISSN-L)
- 1469-445X
- OpenAlex
- W2152660257
- Cited by
- 208
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 8 · 2015: 7 · 2014: 6 · 2013: 16 · 2012: 17
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Experimental Physiology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- angiotensin-converting enzyme, ACE I/D polymorphism, skeletal muscle hypertrophy, resistance training, functional overload, quadriceps strength, isometric training, dynamic training, renin-angiotensin system, muscle atrophy
- MeSH terms
- Adolescent, Adult, Alleles, Genotype, Humans, Hypertrophy, Isoenzymes, Isometric Contraction, Peptidyl-Dipeptidase A, Male, Physical Fitness, Polymorphism, Genetic, Exercise, Polymerase Chain Reaction, Weight-Bearing, Muscle, Skeletal
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