Top

Published in:

22-10-2022 | Original Article

Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial

Authors: Tórur Sjúrðarson, Jacob Bejder, Andreas Breenfeldt Andersen, Thomas C. Bonne, Kasper Kyhl, Martin Thomassen, Júlia Prats, Noomi Oddmarsdóttir Gregersen, May-Britt Skoradal, Pál Weihe, Nikolai B. Nordsborg, Magni Mohr

Published in: European Journal of Applied Physiology | Issue 2/2023

Abstract

Purpose

Angiotensin-converting enzyme (ACE) inhibitor treatment is widely applied, but the fact that plasma ACE activity is a potential determinant of training-induced local muscular adaptability is often neglected. Thus, we investigated the hypothesis that ACE inhibition modulates the response to systematic aerobic exercise training on leg and arm muscular adaptations.

Methods

Healthy, untrained, middle-aged participants (40 ± 7 yrs) completed a randomized, double-blinded, placebo-controlled trial. Participants were randomized to placebo (PLA: CaCO₃) or ACE inhibitor (ACE_i: enalapril) for 8 weeks and completed a supervised, high-intensity exercise training program. Muscular characteristics in the leg and arm were extensively evaluated pre and post-intervention.

Results

Forty-eight participants (n_ACEi = 23, n_PLA = 25) completed the trial. Exercise training compliance was above 99%. After training, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity were increased in m. vastus lateralis in both groups (all P < 0.05) without statistical differences between them (all time × treatment P > 0.05). In m. deltoideus, citrate synthase maximal activity was upregulated to a greater extent (time × treatment P < 0.05) in PLA (51 [33;69] %) than in ACE_i (28 [13;43] %), but the change in 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity was similar between groups. Finally, the training-induced changes in the platelet endothelial cell adhesion molecule-1 protein abundance, a marker of capillary density, were similar in both groups in m. vastus lateralis and m. deltoideus.

Conclusion

Eight weeks of high-intensity whole-body exercise training improves markers of skeletal muscle mitochondrial oxidative capacity, glycolytic capacity and angiogenesis, with no overall effect of pharmacological ACE inhibition in healthy adults.

Bassett DR, Howley ET (2000) Limiting factors for maximum oxygen uptake and determinants of endurance performance./facteurs limitants de la consommation maximale d’oxygene et determinants de la performance d’endurance. Med Sci Sport Exerc 32:70CrossRef

Bergstrom J. Muscle electrolytes in man. Determined by neutron activation analysis on needle biopsy specimens. [Online]. Scand J Clin Lab Investig Vol: 14: S, 1962. https://www.osti.gov/biblio/4636890-muscle-electrolytes-man-determined-neutron-activation-analysis-needle-biopsy-specimens [17 Aug. 2021].

Bray MS, Hagberg JM, Pérusse L, Rankinen T, Roth SM, Wolfarth B, Bouchard C. (2009) The human gene map for performance and health-related fitness phenotypes: The 2006–2007 update.

Camós S, Cruz MJ, Morell F, Solé E (2012) Genetic-based reference values for angiotensin-converting enzyme (ACE) according to I/D polymorphism in a Spanish population sample. Clin Chem Lab Med 50:1749–1753. https://doi.org/10.1515/cclm-2012-0042CrossRef

Cleeter MWJ, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AHV (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for Neurodegenerative Diseases FEBS Lett 345:50–54. https://doi.org/10.1016/0014-5793(94)00424-2CrossRef

Clementi E, Brown GC, Foxwell N, Moncada S (1999) On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci U S A 96:1559–1562. https://doi.org/10.1073/pnas.96.4.1559CrossRef

Cnaan A, Laird NM, Slasor P (1997) Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. Stat Med 16:2349–2380. https://doi.org/10.1002/(SICI)1097-0258(19971030)16:20%3c2349::AID-SIM667%3e3.0.CO;2-ECrossRef

Costa AM, Silva AJ, Garrido ND, Louro H, de Oliveira RJ, Breitenfeld L (2009) Association between ACE D allele and elite short distance swimming. Eur J Appl Physiol 106:785–790. https://doi.org/10.1007/s00421-009-1080-zCrossRef

Flück M, Mathes S, van Ginkel S, Vaughan D, Valdivieso P, Flück M (2015) Gene-Pharmacologial effects on exercise-induced muscle gene expression in healthy men. Anat Physiol. https://doi.org/10.4172/2161-0940.s5-005CrossRef

Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: From marvel to menace. Circulation 113 Lippincott Williams and Wilkins: 1708–1714, 2006.

Förstermann U, Sessa WC. (2012) Nitric oxide synthases: Regulation and function. Eur. Heart J. 33 Oxford University Press: 829

Gibala MJ, Jones AM (2013) Physiological and performance adaptations to high-intensity interval training. Nestle Nutr Inst Workshop Ser 76:51–60. https://doi.org/10.1159/000350256CrossRef

Gibala MJ, McGee SL (2008) Metabolic adaptations to short-term high-intensity interval training: a little pain for a lot of gain? Exerc Sport Sci Rev 36:58–63CrossRef

Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras C, Pallardo FV, Sastre J, Viña J (2008) Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 87:142–149. https://doi.org/10.1093/ajcn/87.1.142CrossRef

Gregersen NO, Apol KD, Weihe P, Steig BÁ, Fargen A G (2021) Bioresource from the faroe genome project. Open J Bioresour. https://doi.org/10.5334/OJB.71CrossRef

Guo Q, Minami N, Mori N, Nagasaka M, Ito O, Kurosawa H, Kanazawa M, Kohzuki M (2010) Effects of estradiol, angiotensin-converting enzyme inhibitor and exercise training on exercise capacity and skeletal muscle in old female rats. Clin Exp Hypertens 32:76–83. https://doi.org/10.3109/10641960902993046CrossRef

Habouzit E, Richard H, Sanchez H, Koulmann N, Serrurier B, Monnet R, Ventura-Clapier R, Bigard X (2009) Decreased muscle ACE activity enhances functional response to endurance training in rats, without change in muscle oxidative capacity or contractile phenotype. J Appl Physiol 107:346–353CrossRef

Helge JW (2010) Arm and leg substrate utilization and muscle adaptation after prolonged low-intensity training. Acta Physiol 199:519–528. https://doi.org/10.1111/j.1748-1716.2010.02123.xCrossRef

Hruskovicová H, Dzurenková D, Selingerová M, Bohuš B, Timkaničová B, Kovács L (2006) The angiotensin converting enzyme I/D polymorphism in long distance runners. J Sports Med Phys Fitness 46:509–513

Imanishi T, Ikejima H, Tsujioka H, Kuroi A, Kobayashi K, Muragaki Y, Mochizuki S, Goto M, Yoshida K, Akasaka T (2008) Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability. Hypertension 51:734–741. https://doi.org/10.1161/HYPERTENSIONAHA.107.104299CrossRef

Kanazawa M, Kawamura T, Li L, Sasaki Y, Matsumoto K, Kataoka H, Ito O, Minami N, Sato T, Ootaka T, Kohzuki M (2006) Combination of exercise and enalapril enhances renoprotective and peripheral effects in rats with renal ablation. Am J Hypertens 19:80–86. https://doi.org/10.1016/j.amjhyper.2005.07.009CrossRef

Kiilerich K, Birk JB, Damsgaard R, Wojtaszewski JFP, Pilegaard H (2008) Regulation of PDH in human arm and leg muscles at rest and during intense exercise. Am J Physiol - Endocrinol Metab 294:36–42. https://doi.org/10.1152/ajpendo.00352.2007CrossRef

Lin MH, Tseng CH, Tseng CC, Huang CH, Chong CK, Tseng CP (2001) Real-time PCR for rapid genotyping of angiotensin-converting enzyme insertion/deletion polymorphism. Clin Biochem 34:661–666. https://doi.org/10.1016/S0009-9120(01)00281-8CrossRef

Lowry OH, Passonneaau J V. A Flexible System of Enzymatic Analysis. Academic Press, 1972.

Ma F, Yang Y, Li X, Zhou F, Gao C, Li M, Gao L (2013) The association of sport performance with ACE and ACTN3 genetic polymorphisms: a systematic review and meta-analysis. PLoS ONE 8:1–9. https://doi.org/10.1371/journal.pone.0054685CrossRef

MacInnis MJ, Gibala MJ (2017) Physiological adaptations to interval training and the role of exercise intensity. J Physiol 595:2915–2930CrossRef

Mahmoudpour SH, Asselbergs FW, Souverein PC, de Boer A, Maitland-van der Zee AH (2018) Prescription patterns of angiotensin-converting enzyme inhibitors for various indications: a UK population-based study. Br J Clin Pharmacol 84:2365–2372. https://doi.org/10.1111/bcp.13692CrossRef

Marcello Iaia F, Perez-Gomez J, Thomassen M, Nordsborg NB, Hellsten Y, Bangsbo J (2011) Relationship between performance at different exercise intensities and skeletal muscle characteristics. J Appl Physiol 110:1555–1563. https://doi.org/10.1152/japplphysiol.00420.2010CrossRef

Mayfield RK, Shimojo N, Jaffa AA (1996) Skeletal muscle kallikrein: Potential role in metabolic regulation. In: Diabetes. https://pubmed.ncbi.nlm.nih.gov/8529795/

Minami N, Li Y, Guo Q, Kawamura T, Mori N, Nagasaka M, Ogawa M, Ito O, Kurosawa H, Kanazawa M, Kohzuki M (2007) Effects of angiotensin-converting enzyme inhibitor and exercise training on exercise capacity and skeletal muscle. J Hypertens 25:1241–1248. https://doi.org/10.1097/HJH.0b013e3280e126bfCrossRef

Mohr M, Nielsen TS, Weihe P, Thomsen JA, Aquino G, Krustrup P, Nordsborg NB (2017) Muscle ion transporters and antioxidative proteins have different adaptive potential in arm than in leg skeletal muscle with exercise training. Physiol Rep 5:1–14. https://doi.org/10.14814/phy2.13470CrossRef

Moncada S, Erusalimsky JD. (2002) Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol. 3 Nature Publishing Group: 214–220

Myerson S, Hemingway H, Budget R, Martin J, Humphries S, Montgomery H (1999) Human angiotensin I-converting enzyme gene and endurance performance. J Appl Physiol 87:1313–1316. https://doi.org/10.1152/jappl.1999.87.4.1313CrossRef

Nazarov IB, Woods DR, Montgomery HE, Shneider O V, Kazakov VI, Tomilin N V, Rogozkin VA. The angiotensin converting enzyme I/D polymorphism in Russian athletes [Online]. Eur J Hum Genet 9: 797–801, 2001. www.nature.com/ejhg [16 Mar. 2022].

Nishida M, Tanabe S, Maruyama Y, Mangmool S, Urayama K, Nagamatsu Y, Takagahara S, Turner JH, Kozasa T, Kobayashi H, Sato Y, Kawanishi T, Inoue R, Nagao T, Kurose H (2005) Gα12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. J Biol Chem 280:18434–18441. https://doi.org/10.1074/jbc.M409710200CrossRef

Nolly H, Carbini LA, Scicli G, Carretero OA, Scicli AG (1994) A local kallikrein-kinin system is present in rat hearts. Hypertension 23:919–923. https://doi.org/10.1161/01.HYP.23.6.919CrossRef

Nordsborg NB, Connolly L, Weihe P, Iuliano E, Krustrup P, Saltin B, Mohr M (2015) Oxidative capacity and glycogen content increase more in arm than leg muscle in sedentary women after intense training. J Appl Physiol 119:116–123. https://doi.org/10.1152/japplphysiol.00101.2015CrossRef

Poderoso JJ, Carreras MC, Lisdero C, Riobó N, Schöpfer F, Boveris A (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328:85–92. https://doi.org/10.1006/abbi.1996.0146CrossRef

Powers SK, Nelson WB, Hudson MB (2011) Exercise-induced oxidative stress in humans: cause and consequences. Free Radic Biol Med 51:942–950CrossRef

Puthucheary Z, Skipworth JRA, Rawal J, Loosemore M, Van Someren K, Montgomery HE (2011) The ACE gene and human performance: 12 Years on. Sport Med 41:433–448CrossRef

Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM (2006) Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 48:914–920. https://doi.org/10.1161/01.HYP.0000244543.91937.79CrossRef

Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346. https://doi.org/10.1172/JCI114844CrossRef

Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106:8665–8670. https://doi.org/10.1073/pnas.0903485106CrossRef

Shen W, Xu X, Ochoa M, Zhao G, Wolin MS, Hintze TH (1994) Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res 75:1086–1095. https://doi.org/10.1161/01.RES.75.6.1086CrossRef

Shen W, Hintze TH, Wolin MS (1995) Nitric oxide: an important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption. Circulation 92:3505–3512. https://doi.org/10.1161/01.CIR.92.12.3505CrossRef

Sjúrðarson T, Bejder J, Andersen AB, Bonne T, Kyhl K, Róin T, Patursson P, Gregersen NO, Skoradal M-B, Schliemann M, Lindegaard M, Weihe P, Mohr M, Nordsborg NB (2022) Effect of angiotensin-converting enzyme inhibition on cardiovascular adaptation to exercise training. Physiol Rep 10:e15382. https://doi.org/10.14814/PHY2.15382CrossRef

Su JB, Barbe F, Crozatier B, Campbell DJ, Hittinger L (1999) Increased bradykinin levels accompany the hemodynamic response to acute inhibition of angiotensin-converting enzyme in dogs with heart failure. J Cardiovasc Pharmacol 34:700–710. https://doi.org/10.1097/00005344-199911000-00012CrossRef

Sumukadas D, Witham MD, Struthers AD, McMurdo MET (2007) Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ 177:867–874. https://doi.org/10.1503/cmaj.061339CrossRef

Sumukadas D, Band M, Miller S, Cvoro V, Witham M, Struthers A, McConnachie A, Lloyd SM, McMurdo M (2014) Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? a randomized controlled trial. Journals Gerontol - Ser A Biol Sci Med Sci 69:736–743. https://doi.org/10.1093/gerona/glt142CrossRef

Sylvén C, Jansson E, Cederholm T, Il Hildebrand, Beermann B (1991) Skeletal muscle depressed calcium and phosphofructokinase in chronic heart failure are upregulated by captopril - a double-blind, placebo-controlled study. J Intern Med 229:171–174. https://doi.org/10.1111/j.1365-2796.1991CrossRef

Thomassen M, Hostrup M, Murphy RM, Cromer BA, Skovgaard C, Gunnarsson TP, Christensen PM, Bangsbo J (2018) Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training. J Appl Physiol 125:470–478. https://doi.org/10.1152/japplphysiol.01042.2017CrossRef

Tsianos G, Sanders J, Dhamrait S, Humphries S, Grant S, Montgomery H (2004) The ACE gene insertion/deletion polymorphism and elite endurance swimming. Eur J Appl Physiol 92:360–362. https://doi.org/10.1007/s00421-004-1120-7CrossRef

van Ginkel S, Ruoss S, Valdivieso P, Degens H, Waldron S, de Haan A, Flück M (2016) ACE inhibition modifies exercise-induced pro-angiogenic and mitochondrial gene transcript expression. Scand J Med Sci Sport 26:1180–1187. https://doi.org/10.1111/sms.12572CrossRef

Vinther A, Alkjær T, Kanstrup IL, Zerahn B, Ekdahl C, Jensen K, Holsgaard-Larsen A, Aagaard P (2013) Slide-based ergometer rowing: effects on force production and neuromuscular activity. Scand J Med Sci Sport 23:635–644. https://doi.org/10.1111/j.1600-0838.2011.01441.xCrossRef

Volianitis S, Yoshiga CC, Secher NH (2020) The physiology of rowing with perspective on training and health. Eur J Appl Physiol 120:1943–1963CrossRef

Wei Y, Sowers JR, Nistala R, Gong H, Uptergrove GME, Clark SE, Morris EM, Szary N, Manrique C, Stump CS (2006) Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem 281:35137–35146. https://doi.org/10.1074/jbc.M601320200CrossRef

Williams AG, Rayson MP, Jubb M, World M, Woods DR, Hayward M, Martin J, Humphries SE, Montgomery HE (2000) The ACE gene and muscle performance. Nature 403:614. https://doi.org/10.1038/35001141CrossRef

Woods D, Hickman M, Jamshidi Y, Brull D, Vassiliou V, Jones A, Humphries S, Montgomery H (2001) Elite swimmers and the D allele of the ACE I/D polymorphism. Hum Genet 108:230–232. https://doi.org/10.1007/s004390100466CrossRef

Woods DR, World M, Rayson MP, Williams AG, Jubb M, Jamshidi Y, Hayward M, Mary DASG, Humphries SE, Montgomery HE (2002) Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training. Eur J Appl Physiol 86:240–244. https://doi.org/10.1007/s00421-001-0545-5CrossRef

Title: Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial
Authors: Tórur Sjúrðarson
Jacob Bejder
Andreas Breenfeldt Andersen
Thomas C. Bonne
Kasper Kyhl
Martin Thomassen
Júlia Prats
Noomi Oddmarsdóttir Gregersen
May-Britt Skoradal
Pál Weihe
Nikolai B. Nordsborg
Magni Mohr
Publication date: 22-10-2022
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Applied Physiology / Issue 2/2023
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI: https://doi.org/10.1007/s00421-022-05072-5

At a glance: The STEP trials

Springer Medicine

Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2023

Knee position sense and knee flexor neuromuscular function are similarly altered after two submaximal eccentric bouts

The effects of α-lactalbumin supplementation and handgrip contraction on soleus motoneuron excitability

Electrical muscle stimulation in young adults: effect of muscle volume on brain-derived neurotrophic factor levels

Differential control of respiratory frequency and tidal volume during exercise

Correction to: The effects of α‑lactalbumin supplementation and handgrip contraction on soleus motoneuron excitability

Effects of α-lactalbumin on strength, fatigue and psychological parameters: a randomised double-blind cross-over study