OpenLB
Open Library of Bioscience
Advanced Search
European journal of applied physiology
Dec 16, 2024;

The MDM2 SNP309 differentially impacts cardiorespiratory fitness in young healthy women and men.

Ghazal Haddadi, Brian Lam, Sokaina Akhtar, Loren Yavelberg, Veronica Jamnik, Emilie Roudier
Author Information
  1. Ghazal Haddadi: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
  2. Brian Lam: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
  3. Sokaina Akhtar: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
  4. Loren Yavelberg: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
  5. Veronica Jamnik: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
  6. Emilie Roudier: School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada. eroudier@yorku.ca. ORCID
PMID: 39681743 DOI: 10.1007/s00421-024-05682-1

Abstract

PURPOSE: Maximal oxygen consumption (VOmax), the predominant index of cardiorespiratory fitness (CRF), is a predictor of whole-body function and longevity in humans. The central cardiac function and the skeletal muscle's capacity to use oxygen are key determinants of VOmax. Murine Double Minute 2 (MDM2), mainly known as an oncogene, could regulate myocardial hypertrophy, skeletal muscle angiogenesis, and oxidative phosphorylation. A prevalent single nucleotide polymorphism in the MDM2 promoter (SNP309) substitutes a T for a G, supporting a greater transcriptional activity. We aim to assess whether SNP309 impacts intrinsic CRF.
METHODS: 82 young healthy nonathletic male and female adults aged 23��������2 years performed cardiorespiratory exercise testing to determine their VOmax (mL kg min). The genomic DNAs isolated from saliva were genotyped using Taqman-based qPCR.
RESULTS: A one-way ANOVA showed that SNP309 influenced relative VOmax in the whole cohort (p���=���0.044) and in men (p���=���0.009), remaining non-significant in women (p���=���0.133). VOmax was higher in TT homozygotes than in GT heterozygotes (whole cohort, 47��������12 vs. 42��������6 mL kg min, p���=���0.030; men, 53��������8 vs. 45��������6 mL kg min, p���=���0.011). A contingency analysis revealed a positive association between SNP309 in men in which the TT genotype was more frequent in the high VOmax group (p���=���0.006). When considering G as the dominant allele, men bearing a G allele had lower relative VOmax than TT homozygotes (47��������7 vs. 53��������8, GG/GT vs. TT, p���=���0.010). Conversely, women bearing a G allele had a higher relative VOmax than TT homozygotes (39��������5 vs. 34��������7, GG/GT vs. TT, p���=���0.047).
CONCLUSION: SNP309 impacts VOmax in a sex-dependent manner in our cohort.

Keywords

Fitness Sex-differences Single nucleotide polymorphism VO2max rs2279744 (MDM2-SNP309)

References

  1. Ahmed S, Egginton S, Jakeman P et al (1997) Is human skeletal muscle capillary supply modelled according to fibre size or fibre type? Exp Physiol 82:231���234. https://doi.org/10.1113/expphysiol.1997.sp004012 [DOI: 10.1113/expphysiol.1997.sp004012]
  2. Aiken J, Roudier E, Ciccone J et al (2016) Phosphorylation of murine double minute-2 on Ser166 is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. FASEB J 30:1120���1134. https://doi.org/10.1096/fj.15-276964 [DOI: 10.1096/fj.15-276964]
  3. Arena G, Ciss�� MY, Pyrdziak S et al (2018) Mitochondrial MDM2 regulates respiratory complex I activity independently of p53. Mol Cell 69:594-609.e8. https://doi.org/10.1016/j.molcel.2018.01.023 [DOI: 10.1016/j.molcel.2018.01.023]
  4. Arva NC, Gopen TR, Talbott KE et al (2005) A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells*. J Biol Chem 280:26776���26787. https://doi.org/10.1074/jbc.M505203200 [DOI: 10.1074/jbc.M505203200]
  5. Besson T, Macchi R, Rossi J et al (2022) Sex differences in endurance running. Sports Med 52:1235���1257. https://doi.org/10.1007/s40279-022-01651-w [DOI: 10.1007/s40279-022-01651-w]
  6. Beyfuss K, Erlich AT, Triolo M, Hood DA (2018) The role of p53 in determining mitochondrial adaptations to endurance training in skeletal muscle. Sci Rep 8:1���14. https://doi.org/10.1038/s41598-018-32887-0 [DOI: 10.1038/s41598-018-32887-0]
  7. Binet ER, McKenna CF, Salvador AF et al (2023) Sex-based comparisons of muscle cellular adaptations after 10 weeks of progressive resistance training in middle-aged adults. J Appl Physiol 134:116���129. https://doi.org/10.1152/japplphysiol.00274.2022 [DOI: 10.1152/japplphysiol.00274.2022]
  8. Blair SN, Church TS (2004) The fitness, obesity, and health equation: is physical activity the common denominator? JAMA 292:1232���1234. https://doi.org/10.1001/jama.292.10.1232 [DOI: 10.1001/jama.292.10.1232]
  9. Bond GL, Hu W, Bond EE et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591���602. https://doi.org/10.1016/j.cell.2004.11.022 [DOI: 10.1016/j.cell.2004.11.022]
  10. Bond GL, Hirshfield KM, Kirchhoff T et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66:5104���5110. https://doi.org/10.1158/0008-5472.CAN-06-0180 [DOI: 10.1158/0008-5472.CAN-06-0180]
  11. Bouchard C, Daw EW, Rice T et al (1998) Familial resemblance for VO2max in the sedentary state: the HERITAGE family study. Med Sci Sports Exerc 30:252���258. https://doi.org/10.1097/00005768-199802000-00013 [DOI: 10.1097/00005768-199802000-00013]
  12. Bouchard C, An P, Rice T et al (1999) Familial aggregation of VO(2max) response to exercise training: results from the HERITAGE Family Study. J Appl Physiol Bethesda Md (1985) 87:1003���1008. https://doi.org/10.1152/jappl.1999.87.3.1003 [DOI: 10.1152/jappl.1999.87.3.1003]
  13. Bouchard C, Rankinen T, Timmons JA (2011) Genomics and genetics in the biology of adaptation to exercise. Compr Physiol 1:1603���1648. https://doi.org/10.1002/cphy.c100059 [DOI: 10.1002/cphy.c100059]
  14. Boulmpou A, Teperikidis E, Papadopoulos C�� et al (2023) The role of cardiopulmonary exercise testing in risk stratification and prognosis of atrial fibrillation: a scoping review of the literature. Acta Cardiol 78:274���287. https://doi.org/10.1080/00015385.2022.2148894 [DOI: 10.1080/00015385.2022.2148894]
  15. Bredin SSD, Gledhill N, Jamnik VK, Warburton DER (2013) PAR-Q+ and ePARmed-X+. Can Fam Physician 59:273���277 [PMID: 23486800]
  16. Broxterman RM, Wagner PD, Richardson RS (2024) Endurance exercise training changes the limitation on muscle V��O2max in normoxia from the capacity to utilize O2 to the capacity to transport O2. J Physiol 602(3):445���459. https://doi.org/10.1113/JP285650 [DOI: 10.1113/JP285650]
  17. Cahalin LP, Chase P, Arena R et al (2013) A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure. Heart Fail Rev 18:79���94. https://doi.org/10.1007/s10741-012-9332-0 [DOI: 10.1007/s10741-012-9332-0]
  18. Card��s J, Marrades RM, Roca J et al (1998) Effects of FIO2 on leg ��VO2 during cycle ergometry in sedentary subjects. Med Sci Sports Exerc 30:697 [DOI: 10.1097/00005768-199805000-00009]
  19. Chen Y-H, Wu H-L, Li C, et al (2006) Anti-angiogenesis mediated by angiostatin K1���3, K1���4 and K1���4.5. Involvement of p53, FasL, AKT and mRNA deregulation. Thromb Haemost 95:668���677
  20. Coggan AR, Spina RJ, King DS et al (1992) Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. J Gerontol 47:B71-76. https://doi.org/10.1093/geronj/47.3.b71 [DOI: 10.1093/geronj/47.3.b71]
  21. Coyle EF, Coggan AR, Hopper MK (1988) Determinants of endurance in well-trained cyclists. J Appl Physiol Bethesda Md 64:2622���2630. https://doi.org/10.1152/jappl.1988.64.6.2622 [DOI: 10.1152/jappl.1988.64.6.2622]
  22. Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582���1584. https://doi.org/10.1126/science.7521539 [DOI: 10.1126/science.7521539]
  23. Economopoulos KP, Sergentanis TN (2010) Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis. Breast Cancer Res Treat 120:211���216. https://doi.org/10.1007/s10549-009-0467-1 [DOI: 10.1007/s10549-009-0467-1]
  24. Espinosa-Ram��rez M, Moya-Gallardo E, Araya-Rom��n F, et al (2021) Sex-differences in the oxygenation levels of intercostal and vastus lateralis muscles during incremental exercise. Front Physiol. https://doi.org/10.3389/fphys.2021.738063
  25. F��hraeus R, Olivares-Illana V (2014) MDM2���s social network. Oncogene 33:4365���4376. https://doi.org/10.1038/onc.2013.410 [DOI: 10.1038/onc.2013.410]
  26. Fu W, Ma Q, Chen L et al (2009) MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 284:13987���14000. https://doi.org/10.1074/jbc.M901758200 [DOI: 10.1074/jbc.M901758200]
  27. Fung H-C, Scholz S, Matarin M et al (2006) Genome-wide genotyping in Parkinson���s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5:911���916. https://doi.org/10.1016/S1474-4422(06)70578-6 [DOI: 10.1016/S1474-4422(06)70578-6]
  28. Ghosh S, Hota M, Chai X et al (2019) Exploring the underlying biology of intrinsic cardiorespiratory fitness through integrative analysis of genomic variants and muscle gene expression profiling. J Appl Physiol Bethesda Md (1985) 126:1292���1314. https://doi.org/10.1152/japplphysiol.00035.2018 [DOI: 10.1152/japplphysiol.00035.2018]
  29. Gledhill N, Cox D, Jamnik R (1994) Endurance athletes��� stroke volume does not plateau: major advantage is diastolic function. Med Sci Sports Exerc 26:1116 [DOI: 10.1249/00005768-199409000-00008]
  30. Gries KJ, Raue U, Perkins RK et al (2018) Cardiovascular and skeletal muscle health with lifelong exercise. J Appl Physiol 125:1636���1645. https://doi.org/10.1152/japplphysiol.00174.2018 [DOI: 10.1152/japplphysiol.00174.2018]
  31. Hagberg JM, McCole SD, Brown MD et al (2002) ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women. J Appl Physiol 92:1083���1088. https://doi.org/10.1152/japplphysiol.00135.2001 [DOI: 10.1152/japplphysiol.00135.2001]
  32. Hancock R, Yavelberg L, Gledhill S et al (2023) Performing one or more verification VO2 workload(s) immediately after an incremental to maximal graded exercise test significantly increases the proportion of participants who meet the job-related aerobic fitness standard for structural firefighters. Eur J Appl Physiol 123:1929���1937. https://doi.org/10.1007/s00421-023-05204-5 [DOI: 10.1007/s00421-023-05204-5]
  33. Hanscombe KB, Persyn E, Traylor M et al (2021) The genetic case for cardiorespiratory fitness as a clinical vital sign and the routine prescription of physical activity in healthcare. Genome Med 13:180. https://doi.org/10.1186/s13073-021-00994-9 [DOI: 10.1186/s13073-021-00994-9]
  34. Haseler LJ, Hogan MC, Richardson RS (1999) Skeletal muscle phosphocreatine recovery in exercise-trained humans is dependent on O2 availability. J Appl Physiol (1985) 86(6):2013���2018. https://doi.org/10.1152/jappl.1999.86.6.2013
  35. Haseler LJ, Lin AP, Richardson RS (2004) Skeletal muscle oxidative metabolism in sedentary humans: 31P-MRS assessment of O2 supply and demand limitations. J Appl Physiol (1985) 97(3):1077���1081. https://doi.org/10.1152/japplphysiol.01321.2003
  36. Hauck L, Stanley-Hasnain S, Fung A et al (2017) Cardiac-specific ablation of the E3 ubiquitin ligase Mdm2 leads to oxidative stress, broad mitochondrial deficiency and early death. PLoS ONE 12:e0189861. https://doi.org/10.1371/journal.pone.0189861 [DOI: 10.1371/journal.pone.0189861]
  37. Hostler D, Schwirian CI, Campos G et al (2001) Skeletal muscle adaptations in elastic resistance-trained young men and women. Eur J Appl Physiol 86:112���118. https://doi.org/10.1007/s004210100495 [DOI: 10.1007/s004210100495]
  38. Hunter SK (2014) Sex differences in human fatigability: mechanisms and insight to physiological responses. Acta Physiol 210:768���789. https://doi.org/10.1111/apha.12234 [DOI: 10.1111/apha.12234]
  39. Jalilvand A, Yari K, Aznab M et al (2020) A case-control study on the SNP309T ��� G and 40-bp Del1518 of the MDM2 gene and a systematic review for MDM2 polymorphisms in the patients with breast cancer. J Clin Lab Anal 34:e23529. https://doi.org/10.1002/jcla.23529 [DOI: 10.1002/jcla.23529]
  40. Jean-Charles P-Y, Yu SM-W, Abraham D et al (2017) Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of ��-adrenergic receptor signaling. JCI Insight 2(e95998):95998. https://doi.org/10.1172/jci.insight.95998 [DOI: 10.1172/jci.insight.95998]
  41. Jones SN, Hancock AR, Vogel H et al (1998) Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A 95:15608���15612. https://doi.org/10.1073/pnas.95.26.15608 [DOI: 10.1073/pnas.95.26.15608]
  42. Kaminsky LA, Arena R, Myers J (2015) Reference standards for cardiorespiratory fitness measured with cardiopulmonary exercise testing: data from the fitness registry and the importance of exercise national database. Mayo Clin Proc 90:1515���1523. https://doi.org/10.1016/j.mayocp.2015.07.026 [DOI: 10.1016/j.mayocp.2015.07.026]
  43. Kenney KL, Wilmore JH, Costill DL (2012) Physiology of sport and exercise. Champaign, 5th edn. Human Kinetics
  44. Klevjer M, Nordeidet AN, Hansen AF et al (2022) Genome-wide association study identifies new genetic determinants of cardiorespiratory fitness: The Tr��ndelag Health Study. Med Sci Sports Exerc 54:1534���1545. https://doi.org/10.1249/MSS.0000000000002951 [DOI: 10.1249/MSS.0000000000002951]
  45. Kodama S, Saito K, Tanaka S et al (2009) Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 301:2024���2035. https://doi.org/10.1001/jama.2009.681 [DOI: 10.1001/jama.2009.681]
  46. Lam B, Roudier E (2019) Considering the role of murine double minute 2 in the cardiovascular system? Front Cell Dev Biol 7:320. https://doi.org/10.3389/fcell.2019.00320 [DOI: 10.3389/fcell.2019.00320]
  47. Lavie CJ, Ozemek C, Carbone S et al (2019) Sedentary behavior, exercise, and cardiovascular health. Circ Res 124:799���815. https://doi.org/10.1161/CIRCRESAHA.118.312669 [DOI: 10.1161/CIRCRESAHA.118.312669]
  48. Layec G, Bringard A, Le Fur Y et al (2015) Opposite effects of hyperoxia on mitochondrial and contractile efficiency in human quadriceps muscles. Am J Physiol-Regul Integr Comp Physiol 308:R724���R733. https://doi.org/10.1152/ajpregu.00461.2014 [DOI: 10.1152/ajpregu.00461.2014]
  49. Lin X, Zhang X, Guo J et al (2015) Effects of exercise training on cardiorespiratory fitness and biomarkers of cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 4:e002014. https://doi.org/10.1161/JAHA.115.002014 [DOI: 10.1161/JAHA.115.002014]
  50. Lolli L, Batterham AM, Weston KL, Atkinson G (2017) Size exponents for scaling maximal oxygen uptake in over 6500 humans: a systematic review and meta-analysis. Sports Med 47:1405���1419. https://doi.org/10.1007/s40279-016-0655-1 [DOI: 10.1007/s40279-016-0655-1]
  51. Matoba S, Kang J-G, Patino WD et al (2006) p53 Regulates mitochondrial respiration. Science 312:1650���1653. https://doi.org/10.1126/science.1126863 [DOI: 10.1126/science.1126863]
  52. Michael D, Oren M (2003) The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 13:49���58. https://doi.org/10.1016/s1044-579x(02)00099-8 [DOI: 10.1016/s1044-579x(02)00099-8]
  53. Milkiewicz M, Roudier E, Doyle JL et al (2011) Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle. Am J Pathol 178:935���944. https://doi.org/10.1016/j.ajpath.2010.10.042 [DOI: 10.1016/j.ajpath.2010.10.042]
  54. Millikan RC, Heard K, Winkel S et al (2006) No association between the MDM2 ���309 T/G promoter polymorphism and breast cancer in african-americans or whites. Cancer Epidemiol Biomarkers Prev 15:175���177. https://doi.org/10.1158/1055-9965.EPI-05-0692 [DOI: 10.1158/1055-9965.EPI-05-0692]
  55. Mitchell EA, Martin NRW, Bailey SJ, Ferguson RA (2018a) Critical power is positively related to skeletal muscle capillarity and type I muscle fibers in endurance-trained individuals. J Appl Physiol 125:737���745. https://doi.org/10.1152/japplphysiol.01126.2017 [DOI: 10.1152/japplphysiol.01126.2017]
  56. Mitchell RA, Schaeffer MR, Ramsook AH et al (2018b) Sex differences in respiratory muscle activation patterns during high-intensity exercise in healthy humans. Respir Physiol Neurobiol 247:57���60. https://doi.org/10.1016/j.resp.2017.09.002 [DOI: 10.1016/j.resp.2017.09.002]
  57. Montgomery HE, Clarkson P, Dollery CM et al (1997) Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation 96:741���747. https://doi.org/10.1161/01.CIR.96.3.741 [DOI: 10.1161/01.CIR.96.3.741]
  58. Muthumani P, Alagarsamy K, Dhandayuthapani S et al (2014) Pro-angiogenic effects of MDM2 through HIF-1�� and NF-��B mediated mechanisms in LNCaP prostate cancer cells. Mol Biol Rep 41:5533���5541. https://doi.org/10.1007/s11033-014-3430-0 [DOI: 10.1007/s11033-014-3430-0]
  59. Nauman J, Nes BM, Lavie CJ et al (2017) Prediction of cardiovascular mortality by estimated cardiorespiratory fitness independent of traditional risk factors: The HUNT Study. Mayo Clin Proc 92:218���227. https://doi.org/10.1016/j.mayocp.2016.10.007 [DOI: 10.1016/j.mayocp.2016.10.007]
  60. Nieminen A-L, Qanungo S, Schneider EA et al (2005) Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia. J Cell Physiol 204:364���369. https://doi.org/10.1002/jcp.20406 [DOI: 10.1002/jcp.20406]
  61. Nwadozi E, Roudier E, Rullman E et al (2016) Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet. FASEB J off Publ Fed Am Soc Exp Biol 30:3039���3052. https://doi.org/10.1096/fj.201600245R [DOI: 10.1096/fj.201600245R]
  62. Olfert IM, Birot O (2011) Importance of anti-angiogenic factors in the regulation of skeletal muscle angiogenesis. Microcirc N Y N (1994) 18:316���330. https://doi.org/10.1111/j.1549-8719.2011.00092.x [DOI: 10.1111/j.1549-8719.2011.00092.x]
  63. Ortiz GJ, Li Y, Post SM et al (2018) Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes. Oncogene 37:332���340. https://doi.org/10.1038/onc.2017.344 [DOI: 10.1038/onc.2017.344]
  64. Park SH, Choi JE, Kim EJ et al (2006) MDM2 309T>G polymorphism and risk of lung cancer in a Korean population. Lung Cancer 54:19���24. https://doi.org/10.1016/j.lungcan.2006.06.008 [DOI: 10.1016/j.lungcan.2006.06.008]
  65. Park J-Y, Wang P, Matsumoto T et al (2009) p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content. Circ Res 105:705���712. https://doi.org/10.1161/CIRCRESAHA.109.205310 [DOI: 10.1161/CIRCRESAHA.109.205310]
  66. Paulin FE, O���Neill M, McGregor G et al (2008) MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism. BMC Cancer 8:281. https://doi.org/10.1186/1471-2407-8-281 [DOI: 10.1186/1471-2407-8-281]
  67. Peterman JE, Arena R, Myers J et al (2020) Development of global reference standards for directly measured cardiorespiratory fitness: a report from the fitness registry and importance of exercise national database (FRIEND). Mayo Clin Proc 95:255���264. https://doi.org/10.1016/j.mayocp.2019.06.013 [DOI: 10.1016/j.mayocp.2019.06.013]
  68. Peterman JE, Arena R, Myers J et al (2021) Reference standards for cardiorespiratory fitness by cardiovascular disease category and testing modality: data from FRIEND. J Am Heart Assoc 10:e022336. https://doi.org/10.1161/JAHA.121.022336 [DOI: 10.1161/JAHA.121.022336]
  69. Phelps M, Darley M, Primrose JN, Blaydes JP (2003) p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Res 63:2616���2623
  70. Porter MM, Stuart S, Boij M, Lexell J (2002) Capillary supply of the tibialis anterior muscle in young, healthy, and moderately active men and women. J Appl Physiol 92:1451���1457. https://doi.org/10.1152/japplphysiol.00744.2001 [DOI: 10.1152/japplphysiol.00744.2001]
  71. Post SM, Quint��s-Cardama A, Pant V et al (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18:220���230. https://doi.org/10.1016/j.ccr.2010.07.010 [DOI: 10.1016/j.ccr.2010.07.010]
  72. Prior SJ, Hagberg JM, Paton CM et al (2006) DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am J Physiol Heart Circ Physiol 290:H1848-1855. https://doi.org/10.1152/ajpheart.01033.2005 [DOI: 10.1152/ajpheart.01033.2005]
  73. Raghuveer G, Hartz J, Lubans D et al (2020) Cardiorespiratory fitness in youth���an important marker of health: a scientific statement from the American Heart Association. Circulation 142:e101���e118. https://doi.org/10.1161/CIR.0000000000000866 [DOI: 10.1161/CIR.0000000000000866]
  74. Roepstorff C, Thiele M, Hillig T et al (2006) Higher skeletal muscle alpha2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise. J Physiol 574:125���138. https://doi.org/10.1113/jphysiol.2006.108720 [DOI: 10.1113/jphysiol.2006.108720]
  75. Ross M, Kargl CK, Ferguson R, Gavin TP, Hellsten Y (2023) Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators. Eur J Appl Physiol 123(7):1415���1432. https://doi.org/10.1007/s00421-022-05128-6 . (Epub 2023 Jan 30) [DOI: 10.1007/s00421-022-05128-6]
  76. Roudier E, Forn P, Perry ME, Birot O (2012) Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. FASEB J off Publ Fed Am Soc Exp Biol 26:4530���4539. https://doi.org/10.1096/fj.12-212720 [DOI: 10.1096/fj.12-212720]
  77. Roudier E, Milkiewicz M, Birot O et al (2013) Endothelial FoxO1 is an intrinsic regulator of thrombospondin 1 expression that restrains angiogenesis in ischemic muscle. Angiogenesis 16:759���772. https://doi.org/10.1007/s10456-013-9353-x [DOI: 10.1007/s10456-013-9353-x]
  78. Salier Eriksson J, Ekblom B, Andersson G, et al (2021) Scaling VO2max to body size differences to evaluate associations to CVD incidence and all-cause mortality risk. BMJ Open Sport Exerc Med 7:e000854. https://doi.org/10.1136/bmjsem-2020-000854
  79. Santisteban KJ, Lovering AT, Halliwill JR, Minson CT (2022) Sex differences in VO2max and the impact on endurance-exercise performance. Int J Environ Res Public Health 19:4946. https://doi.org/10.3390/ijerph19094946 [DOI: 10.3390/ijerph19094946]
  80. Schindler MJ, Adams V, Halle M (2019) Exercise in heart failure-what is the optimal dose to improve pathophysiology and exercise capacity? Curr Heart Fail Rep 16:98���107. https://doi.org/10.1007/s11897-019-00428-z [DOI: 10.1007/s11897-019-00428-z]
  81. Schutte NM, Nederend I, Hudziak JJ et al (2016) Twin-sibling study and meta-analysis on the heritability of maximal oxygen consumption. Physiol Genomics 48:210���219. https://doi.org/10.1152/physiolgenomics.00117.2015 [DOI: 10.1152/physiolgenomics.00117.2015]
  82. Simon-Sanchez J, Scholz S, Fung H-C et al (2007) Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum Mol Genet 16:1���14. https://doi.org/10.1093/hmg/ddl436 [DOI: 10.1093/hmg/ddl436]
  83. Slager SL, Schaid DJ (2001) Case-control studies of genetic markers: power and sample size approximations for Armitage���s test for trend. Hum Hered 52:149���153. https://doi.org/10.1159/000053370 [DOI: 10.1159/000053370]
  84. Slopack D, Roudier E, Liu STK et al (2014) Forkhead BoxO transcription factors restrain exercise-induced angiogenesis. J Physiol 592:4069���4082. https://doi.org/10.1113/jphysiol.2014.275867 [DOI: 10.1113/jphysiol.2014.275867]
  85. Stanley-Hasnain S, Hauck L, Grothe D et al (2017) p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs. Cell Cycle Georget Tex 16:1585���1600. https://doi.org/10.1080/15384101.2017.1346758 [DOI: 10.1080/15384101.2017.1346758]
  86. Stoner M, Wormke M, Saville B et al (2004) Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 23:1052���1063. https://doi.org/10.1038/sj.onc.1207201 [DOI: 10.1038/sj.onc.1207201]
  87. Sundet JM, Magnus P, Tambs K (1994) The heritability of maximal aerobic power: a study of Norwegian twins. Scand J Med Sci Sports 4:181���185. https://doi.org/10.1111/j.1600-0838.1994.tb00423.x [DOI: 10.1111/j.1600-0838.1994.tb00423.x]
  88. Syv��nen A-C (2001) Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet 2:930���942. https://doi.org/10.1038/35103535 [DOI: 10.1038/35103535]
  89. Tabet J-Y, Meurin P, Benzidi Y et al (2013) Greater prognostic value of peak VO2 after exercise training program completion in heart failure patients. Int J Cardiol 168:4139���4144. https://doi.org/10.1016/j.ijcard.2013.07.076 [DOI: 10.1016/j.ijcard.2013.07.076]
  90. Torres SH, Montes de Oca M, Loeb E et al (2011) Gender and skeletal muscle characteristics in subjects with chronic obstructive pulmonary disease. Respir Med 105:88���94. https://doi.org/10.1016/j.rmed.2010.05.010 [DOI: 10.1016/j.rmed.2010.05.010]
  91. Toth A, Nickson P, Qin LL, Erhardt P (2006) Differential regulation of cardiomyocyte survival and hypertrophy by MDM2, an E3 ubiquitin ligase. J Biol Chem 281:3679���3689. https://doi.org/10.1074/jbc.M509630200 [DOI: 10.1074/jbc.M509630200]
  92. Wagner PD (2017) Operation Everest II and the 1978 Habeler/Messner ascent of Everest without bottled O2: what might they have in common? J Appl Physiol 123:1682���1688. https://doi.org/10.1152/japplphysiol.00140.2017 [DOI: 10.1152/japplphysiol.00140.2017]
  93. Wang B, Rasmussen-Ivey C, Little JB, Yuan Z-M (2020) The MDM2/MDMX/p53 axis in the adaptive stress response. Transl Cancer Res 9:1993���1997. https://doi.org/10.21037/tcr.2019.12.89
  94. Weston KS, Wisl��ff U, Coombes JS (2014) High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. Br J Sports Med 48:1227���1234. https://doi.org/10.1136/bjsports-2013-092576 [DOI: 10.1136/bjsports-2013-092576]
  95. Williams CJ, Williams MG, Eynon N et al (2017) Genes to predict VO2max trainability: a systematic review. BMC Genomics 18:831. https://doi.org/10.1186/s12864-017-4192-6 [DOI: 10.1186/s12864-017-4192-6]
  96. Zadro JR, Shirley D, Andrade TB et al (2017) The beneficial effects of physical activity: is it down to your genes? A systematic review and meta-analysis of twin and family studies. Sports Med - Open 3:4. https://doi.org/10.1186/s40798-016-0073-9 [DOI: 10.1186/s40798-016-0073-9]
  97. Zhang X, Pageon L, Post SM (2015) Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer. Oncogene 34:4412���4420. https://doi.org/10.1038/onc.2014.377 [DOI: 10.1038/onc.2014.377]
  98. Zhou S, Gu L, He J et al (2011) MDM2 regulates vascular endothelial growth factor mRNA stabilization in hypoxia ���. Mol Cell Biol 31:4928���4937. https://doi.org/10.1128/MCB.06085-11 [DOI: 10.1128/MCB.06085-11]

Grants

  1. RGPIN-2020-07142DG/Natural Sciences and Engineering Research Council of Canada
  2. 44041/Canadian Foundation for Innovation JLF
Journal Article
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0VOmaxp���=���0SNP309TTvsmenGcardiorespiratoryMDM2impactsrelativecohortwomenhomozygotesalleleoxygenfitnessCRFfunctionskeletalnucleotidepolymorphismyounghealthywholehigher53��������8bearingGG/GTPURPOSE:Maximalconsumptionpredominantindexpredictorwhole-bodylongevityhumanscentralcardiacmuscle'scapacityusekeydeterminantsMurineDoubleMinute2mainlyknownoncogeneregulatemyocardialhypertrophymuscleangiogenesisoxidativephosphorylationprevalentsinglepromotersubstitutesTsupportinggreatertranscriptionalactivityaimassesswhetherintrinsicMETHODS:82nonathleticmalefemaleadultsaged23��������2 yearsperformedexercisetestingdeterminemL kg mingenomicDNAsisolatedsalivagenotypedusingTaqman-basedqPCRRESULTS:one-wayANOVAshowedinfluenced044009remainingnon-significant133GTheterozygotes47��������1242��������6 mL kg min03045��������6 mL kg min011contingencyanalysisrevealedpositiveassociationgenotypefrequenthighgroup006consideringdominantlower47��������7010Conversely39��������534��������7047CONCLUSION:sex-dependentmannerdifferentiallyFitnessSex-differencesSingleVO2maxrs2279744MDM2-SNP309

Similar Articles

Cited By