Nitric Oxide And The Cardiovascular System: Cell Activation, Vascular Reactivity And Genetic Variant [Óxido Nítrico E Sistema Cardiovascular: Ativação Celular, Reatividade Vascular E Variante Genética]

Nitric oxide (NO), primarily identified as an endotheliumderived relaxing factor, is a free radical that signals different biological processes. The identification of NO synthase (NOS) isoforms and the subsequent characterization of the mechanisms of cell activation of the enzymes permitted the partial understanding of both the physiological interactions and of the mechanisms of the diseases in which NO is involved. Mainly expressed in the vascular endothelium, the endothelial NOS isoform (eNOS) plays an important role in the regulation of vascular reactivity and in the development and progression of atherosclerosis. The purpose of this review is to contextualize the reader about the eNOS structure and its mechanisms of cell activation. In view of the advances in molecular biology, we will also address the known mechanisms of gene expression regulation and the role of variants on the genetic code of eNOS associated with cardiovascular phenotypes. Although the importance of NO as an atheroprotective molecule is recognized, our focus will be the review of the literature on NO and its participation in the modulation of the muscle vasodilatation phenotype.9616875Furchgott, R.F., Zawadzki, J.V., The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine (1980) Nature, 288 (5789), pp. 373-376. , DOI 10.1038/288373a0Ignarro, L.J., Buga, G.M., Wood, K.S., Byrns, R.E., Chaudhuri, G., Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide (1987) Proc Natl Acad Sci USA, 84, pp. 9265-9269Vila, E., Salaices, M., Cytokines and vascular reactivity in resistance arteries (2005) Am J Physiol Heart Circ Physiol, 288, pp. H1016-H1021Moncada, S., Palmer, R.M.J., Higgs, E.A., The biological significance of nitric oxide formation from L-arginine (1989) Biochemical Society Transactions, 17 (4), pp. 642-644Kojda, G., Harrison, D., Interactions between NO and reactive oxygen species: Pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure (1999) Cardiovascular Research, 43 (3), pp. 562-571. , DOI 10.1016/S0008-6363(99)00169-8, PII S0008636399001698Palmer, R.M.J., Ferrige, A.G., Moncada, S., Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor (1987) Nature, 327 (6122), pp. 524-526. , DOI 10.1038/327524a0Forstermann, U., Janus-faced role of endothelial NO synthase in vascular disease: Uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal (2006) Biological Chemistry, 387 (12), pp. 1521-1533. , DOI 10.1515/BC.2006.190, PII BCHM387121521Ludmer, P.L., Selwyn, A.P., Shook, T.L., Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries (1986) New England Journal of Medicine, 315 (17), pp. 1046-1051Verma, S., Buchanan, M.R., Anderson, T.J., Endothelial Function Testing as a Biomarker of Vascular Disease (2003) Circulation, 108 (17), pp. 2054-2059. , DOI 10.1161/01.CIR.0000089191.72957.EDPepine, C.J., The impact of nitric oxide in cardiovascular medicine: Untapped potential utility (2009) Am J Med, 122 (5 SUPPL.), pp. S10-S15Madamanchi, N.R., Vendrov, A., Runge, M.S., Oxidative stress and vascular disease (2005) Arterioscler Thromb Vasc Biol, 25, pp. 29-38Cai, H., NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease (2005) Circulation Research, 96 (8), pp. 818-822. , DOI 10.1161/01.RES.0000163631.07205.fbGao, L., Mann, G.E., Vascular NAD(P)H oxidase activation in diabetes: A doubleedged sword in redox signalling (2009) Cardiovasc Res, 82 (1), pp. 9-20De Gennaro Colonna, V., Bianchi, M., Pascale, V., Ferrario, P., Morelli, F., Pascale, W., Asymmetric dimethylarginine (ADMA): An endogenous inhibitor of nitric oxide synthase and a novel cardiovascular risk molecule (2009) Med Sci Monit, 15 (4), pp. RA91-RA101Sessa, W.C., eNOS at a glance (2004) J Cell Sci, 117, pp. 2427-2429Marletta, M.A., Nitric oxide synthase: Aspects concerning structure and catalysis (1994) Cell, 78, pp. 927-930Govers, R., Rabelink, T.J., Cellular regulation of endothelial nitric oxide synthase (2001) Am J Physiol Renal Physiol, 280, pp. F193-F206Stuehr, D.J., Structure-function aspects in the nitric oxide synthases (1997) Annual Review of Pharmacology and Toxicology, 37, pp. 339-359Ferreiro, C.R., Chagas, A.C.P., Carvalho, M.H.C., Dantas, A.P., Scavone, C., Souza, L.C.B., Buffolo, E., Da, L.P.L., Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease (2004) Brazilian Journal of Medical and Biological Research, 37 (9), pp. 1313-1320Andrew, P.J., Mayer, B., Enzymatic function of nitric oxide synthases (1999) Cardiovascular Research, 43 (3), pp. 521-531. , DOI 10.1016/S0008-6363(99)00115-7, PII S0008636399001157Alderton, W.K., Cooper, C.E., Knowles, R.G., Nitric oxide synthases: Structure, function and inhibition (2001) Biochemical Journal, 357 (3), pp. 593-615. , DOI 10.1042/0264-6021:3570593Shaul, P.W., Anderson, R.G., Role of plasmalemmal caveolae in signal transduction (1998) Am J Physiol, 275, pp. L843-L851Wang, X.L., Sim, A.S., Wang, M.X., Murrell, G.A.C., Trudinger, B., Wang, J., Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity (2000) FEBS Letters, 471 (1), pp. 45-50. , DOI 10.1016/S0014-5793(00)01356-9, PII S0014579300013569Garcia-Cardena, G., Martasek, P., Masters, B.S.S., Skidd, P.M., Couet, J., Li, S., Lisanti, M.P., Sessa, W.C., Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo (1997) Journal of Biological Chemistry, 272 (41), pp. 25437-25440. , DOI 10.1074/jbc.272.41.25437Razani, B., Lisanti, M.P., Caveolin-deficient mice: Insights into caveolar function and human disease (2001) Journal of Clinical Investigation, 108 (11), pp. 1553-1561. , DOI 10.1172/JCI200114611Bucci, M., Gratton, J.P., Rudic, R.D., Acevedo, L., Roviezzo, F., Cirino, G., In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation (2000) Nat Med, 6, pp. 1362-1367Wang, X.L., Wang, J., Endothelial nitric oxide synthase gene sequence variations and vascular disease (2000) Mol Genet Metab, 70, pp. 241-251Albrecht, E.W.J.A., Stegeman, C.A., Heeringa, P., Henning, R.H., Van, G.H., Protective role of endothelial nitric oxide synthase (2003) Journal of Pathology, 199 (1), pp. 8-17. , DOI 10.1002/path.1250Griffith, O.W., Stuehr, D.J., Nitric oxide synthases: Properties and catalytic mechanism (1995) Annu Rev Physiol, 57, pp. 707-736Korth, H.G., Sustmann, R., Thater, C., Butler, A.R., Ingold, K.U., On the mechanism of the nitric oxide synthase-catalyzed conversion of N omega-hydroxyl-Larginine to citrulline and nitric oxide (1994) J Biol Chem, 269, pp. 17776-17779Harrison, D.G., Cellular and molecular mechanisms of endothelial cell dysfunction (1997) Journal of Clinical Investigation, 100 (9), pp. 2153-2157Vasquez-Vivar, J., Kalyanaraman, B., Martasek, P., Hogg, N., Masters, B.S.S., Karoui, H., Tordo, P., Pritchard Jr., K.A., Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors (1998) Proceedings of the National Academy of Sciences of the United States of America, 95 (16), pp. 9220-9225. , DOI 10.1073/pnas.95.16.9220Cai, H., Harrison, D.G., Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress (2000) Circ Res, 87, pp. 840-844Klatt, P., Pfeiffer, S., List, B.M., Lehner, D., Glatter, O., Bachinger, H.P., Werner, E.R., Mayer, B., Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin (1996) Journal of Biological Chemistry, 271 (13), pp. 7336-7342. , DOI 10.1074/jbc.271.13.7336Mayer, B., John, M., Heinzel, B., Werner, E.R., Wachter, H., Schultz, G., Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase (1991) FEBS Lett, 288, pp. 187-191Beckman, J.S., Koppenol, W.H., Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly (1996) Am J Physiol, 271, pp. C1424-C1437Searles, C.D., Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression (2006) Am J Physiol Cell Physiol, 291, pp. C803-C816Marsden, P.A., Heng, H.H.Q., Scherer, S.W., Stewart, R.J., Hall, A.V., Shi, X.M., Tsui, L.-C., Schappert, K.T., Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene (1993) Journal of Biological Chemistry, 268 (23), pp. 17478-17488Karantzoulis-Fegaras, F., Antoniou, H., Lai, S.-L.M., Kulkarni, G., D'Abreo, C., Wong, G.K.T., Miller, T.L., Marsden, P.A., Characterization of the human endothelial nitric-oxide synthase promoter (1999) Journal of Biological Chemistry, 274 (5), pp. 3076-3093. , DOI 10.1074/jbc.274.5.3076Malek, A.M., Jiang, L., Lee, I., Sessa, W.C., Izumo, S., Alper, S.L., Induction of nitric oxide synthase mRNA by shear stress requires intracellular calcium and G-protein signals and is modulated by PI 3 kinase (1999) Biochemical and Biophysical Research Communications, 254 (1), pp. 231-242. , DOI 10.1006/bbrc.1998.9921Silacci, P., Formentin, K., Bouzourene, K., Daniel, F., Brunner, H.R., Hayoz, D., Unidirectional and oscillatory shear stress differentially modulate NOS III gene expression (2000) Nitric Oxide, 4, pp. 47-56Davis, M.E., Grumbach, I.M., Fukai, T., Cutchins, A., Harrison, D.G., Shear Stress Regulates Endothelial Nitric-oxide Synthase Promoter Activity through Nuclear Factor kappaB Binding (2004) Journal of Biological Chemistry, 279 (1), pp. 163-168. , DOI 10.1074/jbc.M307528200Davis, M.E., Cai, H., Drummond, G.R., Harrison, D.G., Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways (2001) Circulation Research, 89 (11), pp. 1073-1080Michel, T., Feron, O., Nitric oxide synthases: Which, where, how, and why? (1997) Journal of Clinical Investigation, 100 (9), pp. 2146-2152Zhang, Q., Church, J.E., Jagnandan, D., Catravas, J.D., Sessa, W.C., Fulton, D., Functional relevance of Golgi- And plasma membrane-localized endothelial NO synthase in reconstituted endothelial cells (2006) Arteriosclerosis, Thrombosis, and Vascular Biology, 26 (5), pp. 1015-1021. , DOI 10.1161/01.ATV.0000216044.49494.c4, PII 0004360520060500000012Boo, Y.C., Kim, H.J., Song, H., Fulton, D., Sessa, W., Jo, H., Coordinated regulation of endothelial nitric oxide synthase activity by phosphorylation and subcellular localization (2006) Free Radical Biology and Medicine, 41 (1), pp. 144-153. , DOI 10.1016/j.freeradbiomed.2006.03.024, PII S0891584906002188Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Regulation of endothelium-derived nitric oxide production by the protein kinase Akt (1999) Nature, 399, pp. 597-601Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., Zeiher, A.M., Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation (1999) Nature, 399, pp. 601-605Mount, P.F., Kemp, B.E., Power, D.A., Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation (2007) Journal of Molecular and Cellular Cardiology, 42 (2), pp. 271-279. , DOI 10.1016/j.yjmcc.2006.05.023, PII S0022282806005888Krieger, M.H., Di Lorenzo, A., Sessa, W., Telmisartan reverts endothelial dysfunction (2009) Am J Physiol Cell Physiol, , In pressJoyner, M.J., Dietz, N.M., Nitric oxide and vasodilation in human limbs (1997) Journal of Applied Physiology, 83 (6), pp. 1785-1796Abrahams, V.C., Hilton, S.M., The role of active muscle vasodilatation in the alerting stage of the defence reaction (1964) J Physiol, 171, pp. 189-202Bolme, P., Fuxe, K., Adrenergic and cholinergic nerve terminals in skeletal muscle vessels (1970) Acta Physiol Scand, 78, pp. 52-59Matsukawa, K., Shindo, T., Shirai, M., Ninomiya, I., Nitric oxide mediates cat hindlimb cholinergic vasodilation induced by stimulation of posterior hypothalamus (1993) Japanese Journal of Physiology, 43 (4), pp. 473-483. , DOI 10.2170/jjphysiol.43.473Blair, D.A., Glover, W.E., Greenfield, A.D., Roddie, I.C., Excitation of cholinergic vasodilator nerves to human skeletal muscles during emotional stress (1959) J Physiol, 148, pp. 633-647Dietz, N.M., Rivera, J.M., Warner, D.O., Joyner, M.J., Is nitric oxide involved in cutaneous vasodilation during body heating in humans? (1994) J Appl Physiol, 76, pp. 2047-2053Dietz, N.M., Engelke, K.A., Samuel, T.T., Fix, R.T., Joyner, M.J., Evidence for nitric oxide-mediated sympathetic forearm vasodilatation in humans (1997) Journal of Physiology, 498 (2), pp. 531-540Milner, P., Kirkpatrick, K.A., Ralevic, V., Toothill, V., Pearson, J., Burnstock, G., Endothelial cells cultured from human umbilical vein release ATP, substance P and acetylcholine in response to increased flow (1990) Proc Biol Sci, 241, pp. 245-248Majmudar, N.G., Anumba, D., Robson, S.C., Ford, G.A., Contribution of nitric oxide to beta 2-adrenoceptor mediated vasodilatation in human forearm arterial vasculature (1999) British Journal of Clinical Pharmacology, 47 (2), pp. 173-177. , DOI 10.1046/j.1365-2125.1999.00880.xPoirier, O., Mao, C., Mallet, C., Nicaud, V., Herrmann, S.M., Evans, A., Ruidavets, J.B., Cambien, F., Polymorphisms of the endothelial nitric oxide synthase gene - No consistent association with myocardial infarction in the ECTIM study (1999) European Journal of Clinical Investigation, 29 (4), pp. 284-290. , DOI 10.1046/j.1365-2362.1999.00451.xMiyahara, K., Kawamoto, T., Sase, K., Yui, Y., Toda, K., Yang, L.-X., Hattori, R., Shizuta, Y., Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene (1994) European Journal of Biochemistry, 223 (3), pp. 719-726. , DOI 10.1111/j.1432-1033.1994.tb19045.xPhilip, I., Plantefeve, G., Vuillaumier-Barrot, S., Vicaut, E., LeMarie, C., Henrion, D., Poirier, O., Benessiano, J., G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine (1999) Circulation, 99 (24), pp. 3096-3098Hingorani, A.D., Polymorphisms in endothelial nitric oxide synthase and atherogenesis: John French Lecture 2000 (2001) Atherosclerosis, 154, pp. 521-527Tesauro, M., Thompson, W.C., Rogliani, P., Qi, L., Chaudhary, P.P., Moss, J., Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: Cleavage of proteins with aspartate vs. glutamate at position 298 (2000) Proceedings of the National Academy of Sciences of the United States of America, 97 (6), pp. 2832-2835. , DOI 10.1073/pnas.97.6.2832Fairchild, T.A., Fulton, D., Fontana, J.T., Gratton, J.P., McCabe, T.J., Sessa, W.C., Acidic hydrolysis as a mechanism for the cleavage of the Glu(298) - > Asp variant of human endothelial nitric-oxide synthase (2001) J Biol Chem, 276, pp. 26674-26679Hingorani, A.D., Liang, C.F., Fatibene, J., Lyon, A., Monteith, S., Parsons, A., A common variant of the endothelial nitric oxide synthase (Glu298 - > Asp) is a major risk factor for coronary artery disease in the UK (1999) Circulation, 100, pp. 1515-1520Hibi, K., Ishigami, T., Tamura, K., Mizushima, S., Nyui, N., Fujita, T., Ochiai, H., Umemura, S., Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction (1998) Hypertension, 32 (3), pp. 521-526Shimasaki, Y., Yasue, H., Yoshimura, M., Nakayama, M., Kugiyama, K., Ogawa, H., Harada, E., Nakao, K., Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction (1998) Journal of the American College of Cardiology, 31 (7), pp. 1506-1510. , DOI 10.1016/S0735-1097(98)00167-3, PII S0735109798001673Yoshimura, M., Yasue, H., Nakayama, M., Shimasaki, Y., Sumida, H., Sugiyama, S., Kugiyama, K., Nakao, K., A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese (1998) Human Genetics, 103 (1), pp. 65-69. , DOI 10.1007/s004390050785Miyamoto, Y., Saito, Y., Kajiyama, N., Yoshimura, M., Shimasaki, Y., Nakayama, M., Kamitani, S., Nakao, K., Endothelial nitric oxide synthase gene is positively associated with essential hypertension (1998) Hypertension, 32 (1), pp. 3-8Lacolley, P., Gautier, S., Poirier, O., Pannier, B., Cambien, F., Benetos, A., Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects (1998) Journal of Hypertension, 16 (1), pp. 31-35. , DOI 10.1097/00004872-199816010-00006Kato, N., Sugiyama, T., Morita, H., Nabika, T., Kurihara, H., Yamori, Y., Yazaki, Y., Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension (1999) Hypertension, 33 (4), pp. 933-936Benjafield, A.V., Morris, B.J., Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension (2000) Am J Hypertens, 13, pp. 994-998Vallance, P., Collier, J., Moncada, S., Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man (1989) Lancet, 2, pp. 997-1000Haynes, W.G., Noon, J.P., Walker, B.R., Webb, D.J., Inhibition of nitric oxide synthesis increases blood pressure in healthy humans (1993) Journal of Hypertension, 11 (12), pp. 1375-1380Frandsen, U., Bangsbo, J., Sander, M., Huffner, L., Betak, A., Saltin, B., Hellsten, Y., Exercise-induced hyperaemia and leg oxygen uptake are not altered during effective inhibition of nitric oxide synthase with N G-nitro-L- arginine methyl ester in humans (2001) Journal of Physiology, 531 (1), pp. 257-264. , DOI 10.1111/j.1469-7793.2001.0257j.xFabi, F., Argiolas, L., Chiavarelli, M., Del, B.P., Nitric oxide-dependent and -independent modulation of sympathetic vasoconstriction in the human saphenous vein (1996) European Journal of Pharmacology, 309 (1), pp. 41-50. , DOI 10.1016/0014-2999(96)00316-0Dias, R.G., Alves, M.J., Pereira, A.C., Rondon, M.U., Dos Santos, M.R., Krieger, J.E., Glu298Asp eNOS gene polymorphism causes attenuation in non-exercising muscle vasodilatation (2009) Physiol Genomics, 37 (2), pp. 99-10

Genetic Polymorphisms Determining Of The Physical Performance In Elite Athletes [polimorfismos Genéticos Determinantes Da Performance Física Em Atletas De Elite]

This article is focused on the review of studies looking for "candidate genes" and their relationship with physical performance phenotypes in elite athletes. Our goal is to bring to readers what makes some individuals excel in some sports modalities, based on variants in genetic loci and markers. In addition, we assume the necessity to describe by what mechanisms a gene can contribute in physical performance, detailing in each part the cellular, physiological and molecular pathways involved. For this reason, we limited our discussion to a small number of genetic variants: polymorphisms R577X α-actinin 3 gene (ACTN3), C34T AMP deaminase gene (AMPD1), I/D angiotensin converting enzyme gene (ACE), -9/+9 β 2 bradykinin receptor gene (BDKRB2), and 985+185/1170 creatine kinase M gene (CK-M). We hope that this article bring some new information and refine the knowledge to the fact that the process of talent identification and an individual athletic potential maximization resulting in sport success are strongly associated with genetic variants.133209216Wolfarth, B., Rivera, M.A., Oppert, J.M., Boulay, M.R., Dionne, F.T., Chagnon, M., A polymorphism in the alpha2a-adrenoceptor gene and endurance athlete status (2000) Med Sci Sports Exerc, 32, pp. 1709-1712Rankinen, T., Perusse, L., Gagnon, J., Chagnon, Y.C., Leon, A.C., Skinner, J.S., Angiotensin-converting enzyme ID polymorphism and fitness phenotype in the HERITAGE Family Study (2000) J Appl Physiol, 88, pp. 1029-1035Payne, J., Montgomery, H., The renin-angiotensin system and physical performance (2003) Biochem Soc Trans, 31, pp. 1286-1289Wolfarth, B., Bray, M.S., Hagberg, J.M., Perusse, L., Rauramaa, R., Rivera, M.A., The human gene map for performance and health-related fitness phenotypes: The 2004 update (2005) Med Sci Sports Exerc, 37, pp. 881-903MacArthur, D.G., North, K.N., A gene for speed? The evolution and function of alpha-actinin-3 (2004) Bioessays, 26, pp. 786-795Simoneau, J.A., Bouchard, C., Genetic determinism of fiber type proportion in human skeletal muscle (1995) FASEB J, 9, pp. 1091-1095Scott, W., Stevens, J., Binder-Macleod, S.A., Human skeletal muscle fiber type classifications (2001) Phys Ther, 81, pp. 1810-1816Clarkson, P.M., Devaney, J.M., Gordish-Dressman, H., Thompson, P.D., Hubal, M.J., Urso, M., ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women (2005) J Appl Physiol, 99, pp. 154-163Blanchard, A., Ohanian, V., Critchley, D., The structure and function of alpha-actinin (1989) J Muscle Res Cell Motil, 10, pp. 280-289Yang, N., MacArthur, D.G., Gulbin, J.P., Hahn, A.G., Beggs, A.H., Easteal, S., ACTN3 genotype is associated with human elite athletic performance (2003) Am J Hum Genet, 73, pp. 627-631Noegel, A., Witke, W., Schleicher, M., Calcium-sensitive non-muscle alpha-actinin contains EF-hand structures and highly conserved regions (1987) FEBS Lett, 221, pp. 391-396Gimona, M., Djinovic-Carugo, K., Kranewitter, W.J., Winder, S.J., Functional plasticity of CH domains (2002) FEBS Lett, 513, pp. 98-106North, K.N., Beggs, A.H., Deficiency of a skeletal muscle isoform of alpha-actinin (alpha-actinin-3) in merosin-positive congenital muscular dystrophy (1996) Neuromuscul Disord, 6, pp. 229-235North, K.N., Yang, N., Wattanasirichaigoon, D., Mills, M., Easteal, S., Beggs, A.H., A common nonsense mutation results in alpha-actinin-3 deficiency in the general population (1999) Nat Genet, 21, pp. 353-354Mills, M., Yang, N., Weinberger, R., Vander Woude, D.L., Beggs, A.H., Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: Implications for the evolution of functional redundancy (2001) Hum Mol Genet, 10, pp. 1335-1346Cheetham, M.E., Boobis, L.H., Brooks, S., Williams, C., Human muscle metabolism during sprint running (1986) J Appl Physiol, 61, pp. 54-60Stathis, C.G., Febbraio, M.A., Carey, M.F., Snow, R.J., Influence of sprint training on human skeletal muscle purine nucleotide metabolism (1994) J Appl Physiol, 76, pp. 1802-1809Norman, B., Sabina, R.L., Jansson, E., Regulation of skeletal muscle ATP catabolism by AMPD1 genotype during sprint exercise in asymptomatic subjects (2001) J Appl Physiol, 91, pp. 258-264Westerblad, H., Dahlstedt, A.J., Lannergren, J., Mechanisms underlying reduced maximum shortening velocity during fatigue of intact, single fibres of mouse muscle (1998) J Physiol, 510 (PART 1), pp. 269-277Sabina, R.L., Morisaki, T., Clarke, P., Eddy, R., Shows, T.B., Morton, C.C., Characterization of the human and rat myoadenylate deaminase genes (1990) J Biol Chem, 265, pp. 9423-9433Fishbein, W.N., Sabina, R.L., Ogasawara, N., Holmes, E.W., Immunologic evidence for three isoforms of AMP deaminase (AMPD) in mature skeletal muscle (1993) Biochim Biophys Acta, 1163, pp. 97-104Van Kuppevelt, T.H., Veerkamp, J.H., Fishbein, W.N., Ogasawara, N., Sabina, R.L., Immunolocalization of AMP-deaminase isozymes in human skeletal muscle and cultured muscle cells: Concentration of isoform M at the neuromuscular junction (1994) J Histochem Cytochem, 42, pp. 861-868Morisaki, T., Gross, M., Morisaki, H., Pongratz, D., Zollner, N., Holmes, E.W., Molecular basis of AMP deaminase deficiency in skeletal muscle (1992) Proc Natl Acad Sci U S A, 89, pp. 6457-6461Norman, B., Mahnke-Zizelman, D.K., Vallis, A., Sabina, R.L., Genetic and other determinants of AMP deaminase activity in healthy adult skeletal muscle (1998) J Appl Physiol, 85, pp. 1273-1278Fishbein, W.N., Armbrustmacher, V.W., Griffin, J.L., Myoadenylate deaminase deficiency: A new disease of muscle (1978) Science, 200, pp. 545-548Kar, N.C., Pearson, C.M., Muscle adenylate deaminase deficiency. Report of six new cases (1981) Arch Neurol, 38, pp. 279-281Bogdanis, G.C., Nevill, M.E., Boobis, L.H., Lakomy, H.K., Nevill, A.M., Recovery of power output and muscle metabolites following 30 s of maximal sprint cycling in man (1995) J Physiol, 482 (PART 2), pp. 467-480Hargreaves, M., McKenna, M.J., Jenkins, D.G., Warmington, S.A., Li, J.L., Snow, R.J., Muscle metabolites and performance during high-intensity, intermittent exercise (1998) J Appl Physiol, 84, pp. 1687-1691Hellsten, Y., Maclean, D., Radegran, G., Saltin, B., Bangsbo, J., Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle (1998) Circulation, 98, pp. 6-8MacLean, D.A., Sinoway, L.I., Leuenberger, U., Systemic hypoxia elevates skeletal muscle interstitial adenosine levels in humans (1998) Circulation, 98, pp. 1990-1992Winder, W.W., Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle (2001) J Appl Physiol, 91, pp. 1017-1028Rico-Sanz, J., Rankinen, T., Joanisse, D.R., Leon, A.S., Skinner, J.S., Wimore, J.H., Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study (2003) Physiol Genomics, 14, pp. 161-166Rubio, J.C., Martin, M.A., Rabadan, M., Gomez-Gallego, F., San Juan, A.F., Alonso, J.M., Frequency of the C34T mutation of the AMPD1 gene in world-class endurance athletes: Does this mutation impair performance? (2005) J Appl Physiol, 98, pp. 2108-2112Broberg, S., Sahlin, K., Adenine nucleotide degradation in human skeletal muscle during prolonged exercise (1989) J Appl Physiol, 67, pp. 116-122Norman, B., Sollevi, A., Jansson, E., Increased IMP content in glycogen-depleted muscle fibres during submaximal exercise in man (1988) Acta Physiol Scand, 133, pp. 97-100Sahlin, K., Katz, A., Broberg, S., Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise (1990) Am J Physiol, 259, pp. C834-C841Myerson, S., Hemingway, H., Budget, R., Martin, J., Humphries, S., Montgomery, H., Human angiotensin I-converting enzyme gene and endurance performance (1999) J Appl Physiol, 87, pp. 1313-1316Dzau, V.J., Circulating versus local renin-angiotensin system in cardiovascular homeostasis (1988) Circulation, 77, pp. I4-13Myerson, S.G., Montgomery, H.E., Whittingham, M., Budget, R., Martin, J., Humphries, S., Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: A randomized controlled trial with losartan (2001) Circulation, 103, pp. 226-230Jonsson, J.R., Game, P.A., Head, R.J., Frewin, D.B., The expression and localization of the angiotensin-converting enzyme mRNA in human adipose tissue (1994) Blood Press, 3, pp. 72-75Dragovic, T., Minshall, R., Jackman, H.L., Wang, L.X., Erdos, E.G., Kininase II-type enzymes. Their putative role in muscle energy metabolism (1996) Diabetes, 45 (SUPPL. 1), pp. S34-S37Coates, D., The angiotensin converting enzyme (ACE) (2003) Int J Biochem Cell Biol, 35, pp. 769-773Williams, A.G., Dhamrait, S.S., Wootton, P.T., Day, S.H., Hawe, E., Payne, J.R., Bradykinin receptor gene variant and human physical performance (2004) J Appl Physiol, 96, pp. 938-942Costerousse, O., Allegrini, J., Lopez, M., Alhenc-Gelas, F., Angiotensin I-converting enzyme in human circulating mononuclear cells: Genetic polymorphism of expression in T-lymphocytes (1993) Biochem J, 290 (PART 1), pp. 33-40Danser, A.H., Schalekamp, M.A., Bax, W.A., van den Brink, A.M., Saxena, P.R., Riegger, G.A., Angiotensin-converting enzyme in the human heart. Effect of the deletion/ insertion polymorphism (1995) Circulation, 92, pp. 1387-1388Hagberg, J.M., Ferrell, R.E., McCole, S.D., Wilund, K.R., Moore, G.E., V̇O 2 max is associated with ACE genotype in postmenopausal women (1998) J Appl Physiol, 85, pp. 1842-1846Touyz, R.M., Deng, L.Y., He, G., Wu, X.H., Schiffrin, E.L., Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: Role of extracellular signal-regulated kinases (1999) J Hypertens, 17, pp. 907-916Kauma, H., Ikaheimo, M., Savolainen, M.J., Kiema, T.R., Rantala, A.O., Lilja, M., Variants of renin-angiotensin system genes and echocardiographic left ventricular mass (1998) Eur Heart J, 19, pp. 1109-1117Linhart, A., Sedlacek, K., Jachymova, M., Jindra, A., Beran, S., Vondracek, V., Lack of association of angiotensin-converting enzyme and angiotensinogen genes polymorphisms with left ventricular structure in young normotensive men (2000) Blood Press, 9, pp. 47-51Kinugawa, T., Ogino, K., Miyakoda, H., Saitoh, M., Hisatome, I., Fujimoto, Y., Responses of catecholamines, renin-angiotensin system, and atrial natriuretic peptide to exercise in untrained men and women (1997) Gen Pharmacol, 28, pp. 225-228Higaki, J., Aoki, M., Morishita, R., Kida, I., Taniyama, Y., Tomita, N., In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy (2000) Arterioscler Thromb Vasc Biol, 20, pp. 428-434Douglas, P.S., O'Toole, M.L., Katz, S.E., Ginsburg, G.S., Hiller, W.D., Laird, R.H., Left ventricular hypertrophy in athletes (1997) Am J Cardiol, 80, pp. 1384-1388Hernandez, D., de la Rosa, A., Barragan, A., Barrios, Y., Salido, E., Torres, A., The ACE/DD genotype is associated with the extent of exercise-induced left ventricular growth in endurance athletes (2003) J Am Coll Cardiol, 42, pp. 527-532Montgomery, H., Clarkson, P., Barnard, M., Bell, J., Brynes, A., Dollery, C., Angiotensin-converting enzyme gene insertion/deletion polymorphism and response to physical training (1999) Lancet, 353, pp. 541-545Williams AG, Rayson MP, Jubb M, World M, Woods DR, Hayward M, et al. The ACE gene and muscle performance. Nature. 2000;403:614Zhao, G., Bernstein, R.D., Hintze, T.H., Nitric oxide and oxygen utilization: Exercise, heart failure and diabetes (1999) Coron Artery Dis, 10, pp. 315-320Zhang, B., Tanaka, H., Shono, N., Miura, S., Kiyonaga, A., Shindo, M., The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle (2003) Clin Genet, 63, pp. 139-144Wicklmayr, M., Dietze, G., Brunnbauer, H., Rett, K., Mehnert, H., Dose-dependent effect of bradykinin on muscular blood flow and glucose uptake in man (1983) Hoppe Seylers Z Physiol Chem, 364, pp. 831-833Brull D, Dhamrait S, Myerson S, Erdmann J, Woods D, World M, et al. Bradykinin B2BKR receptor polymorphism and left-ventricular growth response. Lancet. 2001;358:1155-6Figueroa, C.D., Dietze, G., Muller-Esterl, W., Immunolocalization of bradykinin B2 receptors on skeletal muscle cells (1996) Diabetes, 45 (SUPPL. 1), pp. S24-S28Langberg, H., Bjorn, C., Boushel, R., Hellsten, Y., Kjaer, M., Exercise-induced increase in interstitial bradykinin and adenosine concentrations in skeletal muscle and peritendinous tissue in humans (2002) J Physiol, 542, pp. 977-983Taguchi, T., Kishikawa, H., Motoshima, H., Sakai, K., Nishiyama, T., Yoshizato, K., Involvement of bradykinin in acute exercise-induced increase of glucose uptake and GLUT-4 translocation in skeletal muscle: Studies in normal and diabetic humans and rats (2000) Metabolism, 49, pp. 920-930Rabito, S.F., Minshall, R.D., Nakamura, F., Wang, L.X., Bradykinin B2 receptors on skeletal muscle are coupled to inositol 1,4,5-trisphosphate formation (1996) Diabetes, 45 (SUPPL. 1), pp. S29-S33Rivera, M.A., Dionne, F.T., Simoneau, J.A., Perusse, L., Chagnon, M., Chagnon, Y., Muscle-specific creatine kinase gene polymorphism and V̇O 2max in the HERITAGE Family Study (1997) Med Sci Sports Exerc, 29, pp. 1311-1317Echegaray, M., Rivera, M.A., Role of creatine kinase isoenzymes on muscular and cardiorespiratory endurance: Genetic and molecular evidence (2001) Sports Med, 31, pp. 919-934Steeghs, K., Heerschap, A., de Haan, A., Ruitenbeek, W., Oerlemans, F., van Deursen, J., Use of gene targeting for compromising energy homeostasis in neuromuscular tissues: The role of sarcomeric mitochondrial creatine kinase (1997) J Neurosci Methods, 71, pp. 29-41Fontanet, H.L., Trask, R.V., Haas, R.C., Strauss, A.W., Abendschein, D.R., Billadello, J.J., Regulation of expression of M, B, and mitochondrial creatine kinase mRNAs in the left ventricle after pressure overload in rats (1991) Circ Res, 68, pp. 1007-1012Apple, F.S., Billadello, J.J., Expression of creatine kinase M and B mRNAs in treadmill trained rat skeletal muscle (1994) Life Sci, 55, pp. 585-592Rivera, M.A., Perusse, L., Simoneau, J.A., Gagnon, J., Dionne, F.T., Leon, A.S., Linkage between a muscle-specific CK gene marker and V̇O 2max in the HERITAGE Family Study (1999) Med Sci Sports Exerc, 31, pp. 698-701Coerwinkel-Driessen, M., Schepens, J., van Zandvoort, P., van Oost, B., Mariman, E., Wieringa, B., NcoI RFLP at the creatine kinase-muscle type gene locus (CKMM, chromosome 19) (1988) Nucleic Acids Res, 16, p. 8743Sylven, C., Jansson, E., Olin, C., Human myocardial and skeletal muscle enzyme activities: Creatine kinase and its isozyme MB as related to citrate synthase and muscle fibre types (1983) Clin Physiol, 3, pp. 461-468Apple, F.S., Tesch, P.A., CK and LD isozymes in human single muscle fibers in trained athletes (1989) J Appl Physiol, 66, pp. 2717-2720Bittl, J.A., DeLayre, J., Ingwall, J.S., Rate equation for creatine kinase predicts the in vivo reaction velocity: 31P NMR surface coil studies in brain, heart, and skeletal muscle of the living rat (1987) Biochemistry, 26, pp. 6083-6090Sylven, C., Jansson, E., Kallner, A., Book, K., Human creatine kinase. Isoenzymes and logistics of energy distribution (1984) Scand J Clin Lab Invest, 44, pp. 611-615Yamashita, K., Yoshioka, T., Activities of creatine kinase isoenzymes in single skeletal muscle fibres of trained and untrained rats (1992) Pflugers Arch, 421, pp. 270-273Bouchard, C., Leon, A.S., Rao, D.C., Skinner, J.S., Wilmore, J.H., Gagnon, J., The HERITAGE family study. Aims, design, and measurement protocol (1995) Med Sci Sports Exerc, 27, pp. 721-72