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Longitudinal metabolomic profiles reveal sex-specific adjustments to long-duration spaceflight and return to Earth

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Abstract

Spaceflight entails a variety of environmental and psychological stressors that may have long-term physiological and genomic consequences. Metabolomics, an approach that investigates the terminal metabolic outputs of complex physiological alterations, considers the dynamic state of the human body and allows the identification and quantification of down-stream metabolites linked to up-stream physiological and genomic regulation by stress. Employing a metabolomics-based approach, this study investigated longitudinal metabolic perturbations of male (n = 40) and female (n = 11) astronauts on 4–6-month missions to the International Space Station (ISS). Proton nuclear magnetic resonance (1H-NMR) spectroscopy followed by univariate, multivariate and machine learning analyses were used on blood serum to examine sex-specific metabolic changes at various time points throughout the astronauts’ missions, and the metabolic effects of long-duration space travel. Space travel resulted in sex-specific changes in energy metabolism, bone mineral and muscle regulation, immunity, as well as macromolecule maintenance and synthesis. Additionally, metabolic signatures suggest differential metabolic responses—especially during the recovery period—with females requiring more time to adjust to return to Earth. These findings provide insight into the perturbations in glucose and amino acid metabolism and macromolecule biosynthesis that result from the stressors of long-duration spaceflight. Metabolomic biomarkers may provide a viable approach to predicting and diagnosing health risks associated with prolonged space travel and other physiological challenges on Earth.

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References

  1. Kandarpa K, Schneider V, Ganapathy K (2019) Human health during space travel: an overview. Neurol India 67:176–181. https://doi.org/10.4103/0028-3886.259123

    Article  Google Scholar 

  2. Bacal K, Romano J (2016) Radiation health and protection. Space Physiology and Medicine, New York. Springer, NY, pp 197–224

    Chapter  Google Scholar 

  3. Beheshti A, Cekanaviciute E, Smith DJ, Costes SV (2018) Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: a systems biology GeneLab case study. Sci Rep 8:1–10. https://doi.org/10.1038/s41598-018-22613-1

    Article  CAS  Google Scholar 

  4. Kanas N, Manzey D (2008). Space psychology and psychiatry. https://doi.org/10.1007/978-1-4020-6770-9

    Article  Google Scholar 

  5. Mader TH, Gibson CR, Otto CA, Sargsyan AE, Miller NR, Subramanian PS, Hart SF, Lipskey W, Patel NB, Lee AG (2017) Persistent asymmetric optic disc swelling after long-duration space flight: implications for pathogenesis. J Neuroophthalmol 37:133–139. https://doi.org/10.1097/WNO.0000000000000467

    Article  PubMed  Google Scholar 

  6. Smith SM, Heer M, Shackelford LC, Sibonga JD, Spatz J, Pietrzyk RA, Hudson EK, Zwart SR (2015) Bone metabolism and renal stone risk during international space station missions. Bone 81:712–720. https://doi.org/10.1016/j.bone.2015.10.002

    Article  CAS  PubMed  Google Scholar 

  7. Gambara G, Salanova M, Ciciliot S, Furlan S, Gutsmann M, Schiffl G, Ungethuem U, Volpe P, Gynga H-C, Blottner D (2017) Gene expression profiling in slow-type calf soleus muscle of 30 days space-flown mice. PLoS ONE 12:e0169314. https://doi.org/10.1371/journal.pone.0169314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hughson RL (2009) Recent findings in cardiovascular physiology with space travel. Respir Physiol Neurobio 169:S38–S41. https://doi.org/10.1016/j.resp.2009.07.017

    Article  Google Scholar 

  9. Hughson R, Helm A, Durante M (2018) Heart in space: effect of the extraterrestrial environment on the cardiovascular system. Nat Rev Cardiol 15:167–180. https://doi.org/10.1038/nrcardio.2017.157

    Article  PubMed  Google Scholar 

  10. Chakraborty N, Cheema A, Gautam A, Donohue D, Hoke A, Conley C, Jett M, Hammamieh R (2018) Gene-metabolite profile integration to understand the cause of spaceflight induced immunodeficiency. NPJ Micrograv 4:1–9. https://doi.org/10.1038/s41526-017-0038-4

    Article  CAS  Google Scholar 

  11. Stein TP (2002) Space flight and oxidative stress. Nutrition 18:867–871. https://doi.org/10.1016/S0899-9007(02)00938-3

    Article  CAS  PubMed  Google Scholar 

  12. da Silveira WA, Fazelinia H, Rosenthal SB, Laiakis EC, Kim MS, Meydan C, Kidane Y, Rathi KS, Smith SM, Stear B, Ying Y, Zhang Y, Foox J, Zanello S, Crucian B, Wang D, Nugent A, Costa HA, Zwart SR, Schrepfer S, Elworth RAL, Sapoval N, Treangen T, MacKay M, Gokhale NS, Horner SM, Singh LN, Wallace DC, Willey JS, Schisler JC, Meller R, McDonald JT, Fisch KM, Hardiman G, Taylor D, Mason CE, Costes SV, Beheshti A (2020) Comprehensive multi-omics analysis reveals mitochondrial stress as a central biological hub for spaceflight impact. Cell 183:1185–1201. https://doi.org/10.1016/j.cell.2020.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tauber S, Lauber BA, Paulsen K, Layer LE, Lehmann M, Hauschild S, Sheperd NR, Polzer J, Segerer J, Thiel CS, Ullrich O (2017) Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity. PLoS ONE 12:e0175599. https://doi.org/10.1371/journal.pone.0175599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kumar A, Tahimic CGT, Almeida EAC, Globus RK (2021) Spaceflight modulates the expression of key oxidative stress and cell cycle related genes in heart. Int J Mol Sci 22:9088. https://doi.org/10.3390/ijms22169088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stowe RP, Sams CF, Pierson DL (2003) Effects of mission duration on neuroimmune responses in astronauts. Aviat Space Environ Med 74(12):1281–1284

    PubMed  Google Scholar 

  16. Strewe C, Feuerecker M, Nichiporuk I, Kaufmann I, Hauer D, Morukov B, Schelling G, Choukèr A (2012) Effects of parabolic flight and spaceflight on the endocannabinoid system in humans. Rev Neurosci 23:673–680. https://doi.org/10.1515/revneuro-2012-0057

    Article  CAS  PubMed  Google Scholar 

  17. Strollo F, Vernikos J (2021) Aging-like metabolic and adrenal changes in microgravity: State of the art in preparation for Mars. Neurosci Biobehav Rev 126:236–242. https://doi.org/10.1016/j.neubiorev.2021.01.028

    Article  CAS  PubMed  Google Scholar 

  18. Nicholson JK, Lindon JC, Holmes E (1999) “Metabonomics”: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181–1189. https://doi.org/10.1080/004982599238047

    Article  CAS  PubMed  Google Scholar 

  19. Gil RB, Lehmann R, Schmitt-Kopplin P, Heinzmann SS (2016) 1H NMR-based metabolite profiling workflow to reduce inter-sample chemical shift variations in urine samples for improved biomarker discovery. Anal Bioanal Chem 408:4683–4691. https://doi.org/10.1007/s00216-016-9552-6

    Article  CAS  PubMed  Google Scholar 

  20. Schmidt MA, Meydan C, Schmidt CM, Afshinnekoo E, Mason CE (2020) The NASA twins study: the effect of one year in space on long-chain fatty acid desaturases and elongases. Lifestyle Genom 13:107–121. https://doi.org/10.1159/000506769

    Article  CAS  PubMed  Google Scholar 

  21. Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR et al (2019) The NASA twins study: a multidimensional analysis of a year-long human spaceflight. Science 364:eaau8650. https://doi.org/10.1126/science.aau8650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Šket R, Deutsch L, Prevoršek Z, Mekjavić IB, Plavec J, Rittweger J, Debevec T, Eiken O, Stres B (2020) Systems view of deconditioning during spaceflight simulation in the PlanHab Project: the departure of urine 1H-NMR metabolomes from healthy state in young males subjected to bedrest inactivity and hypoxia. Front Physiol 11:1550. https://doi.org/10.3389/fphys.2020.532271

    Article  Google Scholar 

  23. Loerch LH (2015) Exercise countermeasures on ISS: summary and future directions. Aerosp Med Hum Perform 86:A92–A94

    Article  PubMed  Google Scholar 

  24. Korth DW (2015) Exercise countermeasure hardware evolution on ISS: the first decade. Aerosp Med Hum Perform 86:A7–A13

    Article  PubMed  Google Scholar 

  25. Smith SM, Zwart SR, Douglas GL, Heer M (2021) Human adaptation to spaceflight: the role of food and nutrition, 2nd edition (NP-2021-03-003-JSC). National Aeronautics and Space Administration Lyndon B. Johnson Space Center, Houston, TX

    Google Scholar 

  26. Smith SM, Heer M, Wang Z, Huntoon CL, Zwart SR (2012) Long-duration space flight and bed rest effects on testosterone and other steroids. J Clin Endocrin Metab 97:270–278. https://doi.org/10.1210/jc.2011-2233

    Article  CAS  Google Scholar 

  27. Psychogios N, Hau DD, Peng J, Guo AC, Mandal R, Bouatra S, Sinelnikov I, Krishnamurthy R, Eisner R, Gautam B, Young N, Xia J, Knox C, Dong E, Huang P, Hollander Z, Pederson TL, Smith SR, Bamforth F, Greiner R, McManus B, Newman JW, Goodfriend T, Wishart DS (2011) The human serum metabolome PLOS ONE 6:e16957. https://doi.org/10.1371/journal.pone.0016957

    Article  CAS  PubMed  Google Scholar 

  28. Craig A, Cloarec O, Holmes E, Nicholson JK, Lindon JC (2006) Scaling and normalization effects in NMR spectroscopic metabonomic data sets. Anal Chem (Washington) 78:2262–2267. https://doi.org/10.1021/ac0519312

    Article  CAS  Google Scholar 

  29. Anderson PE, Mahle DA, Doom TE, Reo NV, DelRaso NJ, Raymer ML (2011) Dynamic adaptive binning: an improved quantification technique for NMR spectroscopic data. Metabolomics 7:179–190. https://doi.org/10.1007/s11306-010-0242-7

    Article  CAS  Google Scholar 

  30. Worley B, Powers R (2013) Multivariate analysis in metabolomics. Current. Metabolomics 1:92–107

    CAS  Google Scholar 

  31. Yun Y-H, Liang F, Deng B-C, Lai G-B, Gonçalves CMV, Lu H-M, Yan J, Huang X, Yi L-Z, Liang Y-Z (2015) Informative metabolites identification by variable importance analysis based on random variable combination. Metabolomics 11:1539–1551. https://doi.org/10.1007/s11306-015-0803-x

    Article  CAS  Google Scholar 

  32. Goodpaster AM, Romick-Rosendale LE, Kennedy MA (2010) Statistical significance analysis of nuclear magnetic resonance-based metabonomics data. Anal Biochem 401:134–143. https://doi.org/10.1016/j.ab.2010.02.005

    Article  CAS  PubMed  Google Scholar 

  33. Tai YC, Speed TP (2006) A multivariate empirical bayes statistic for replicated Microarray time course data. Ann Stats 34:2387–2412. https://doi.org/10.1214/009053606000000759

    Article  Google Scholar 

  34. Xia J, Wishart DS (2016) Using MetaboAnalyst 30 for comprehensive metabolomics data analysis. Curr Prot Bioinform. https://doi.org/10.1002/cpbi.11

    Article  Google Scholar 

  35. Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart D, Xia J (2018) MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 46:W486–W494. https://doi.org/10.1093/nar/gky310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weljie AM, Newton J, Mercier P, Carlson E, Slupsky CM (2006) Targeted profiling: quantitative analysis of 1H NMR metabolomics data. Anal Chem 78:4430–4442. https://doi.org/10.1021/ac060209g

    Article  CAS  PubMed  Google Scholar 

  37. Xia J, Wishart DS (2010) MSEA: a web-based tool to identify biologically meaningful patterns in quantitative metabolomic data. Nucleic Acids Res 38:W71–W77. https://doi.org/10.1093/nar/gkq329f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wishart D, Tzur D, Knox C, Eisner R, Guo A, Young N (2007) HMDB: the human metabolome database. Nucleic Acids Res 35:D521-526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, Djoumbou Y, Mandal R, Aziat F, Dong E (2013) HMDB 3.0—the human metabolome database in 2013. Nucleic Acids Res 41:D801–D807. https://doi.org/10.1093/nar/gks1065

    Article  CAS  PubMed  Google Scholar 

  40. Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B, Hau DD, Psychogios N, Dong E, Bouatra S (2009) HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res 37:D603–D610. https://doi.org/10.1093/nar/gkn810

    Article  CAS  PubMed  Google Scholar 

  41. Xia J, Wishart DS (2010) MetPA: a web-based metabolomics tool for pathway analysis and visualization. Bioinformatics 26:2342–2344. https://doi.org/10.1093/bioinformatics/btq418

    Article  CAS  PubMed  Google Scholar 

  42. Chong J, Wishart DS, Xia J (2019) Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinf 68:e86. https://doi.org/10.1002/cpbi.86

    Article  Google Scholar 

  43. Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30. https://doi.org/10.1093/nar/28.1.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M (2019) New approach for understanding genome variations in KEGG. Nucleic Acids Res 47:D590–D595. https://doi.org/10.1093/nar/gky962

    Article  CAS  PubMed  Google Scholar 

  45. Endler NS (2004) The joint effects of person and situation factors on stress in spaceflight. Aviat Space Environ Med 75:C22–C27

    PubMed  Google Scholar 

  46. Costanzo M, Caterino M, Sotgiu G, Ruoppolo M, Franconi F, Campesi I (2022) Sex differences in the human metabolome. Biol Sex Differ 13:30. https://doi.org/10.1186/s13293-022-00440-4

    Article  PubMed  PubMed Central  Google Scholar 

  47. Melkonian EA, Asuka E, Schury MP (2019) Physiology, Gluconeogenesis. StatPearls Publishing, Treasure Island (FL)

    Google Scholar 

  48. Williams D, Kuipers A, Mukai C, Thirsk R (2009) Acclimation during space flight: effects on human physiology. Can Med Assoc J 180:1317–1323. https://doi.org/10.1503/cmaj.090628

    Article  Google Scholar 

  49. Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M (2021) KEGG: integrating viruses and cellular organisms. Nucleic Acids Res 49:D545–D551. https://doi.org/10.1093/nar/gkaa970

    Article  CAS  PubMed  Google Scholar 

  50. Kanehisa M (2000) Post-genome informatics. OUP Oxford University Press, Oxford

    Google Scholar 

  51. Hers HG, Hue L (1983) Gluconeogenesis and related aspects of glycolysis. Ann Review Biochem 52:617–653. https://doi.org/10.1146/annurev.bi.52.070183.003153

    Article  CAS  Google Scholar 

  52. Fitts RH, Colloton PA, Trappe SW, Costill DL, Bain JLW, Riley DA (2013) Effects of prolonged space flight on human skeletal muscle enzyme and substrate profiles. J Appl Phys 115:667–679. https://doi.org/10.1152/japplphysiol.00489.2013

    Article  CAS  Google Scholar 

  53. Wang Y, Javed I, Liu Y, Lu S, Peng G, Zhang Y, Qing H, Deng Y (2016) Effect of prolonged simulated microgravity on metabolic proteins in rat hippocampus: steps toward safe space travel. J Prot Res 15:29–37. https://doi.org/10.1021/acs.jproteome.5b00777

    Article  CAS  Google Scholar 

  54. Gray LR, Tompkins SC, Taylor EB (2014) Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci 71:2577–2604. https://doi.org/10.1007/s00018-013-1539-2

    Article  CAS  PubMed  Google Scholar 

  55. Leonardi R, Jackowski S, Begley TJ (2007) Biosynthesis of pantothenic acid and coenzyme A. EcoSal Plus. https://doi.org/10.1128/ecosalplus.3.6.3.4

    Article  PubMed  PubMed Central  Google Scholar 

  56. Czumaj A, Szrok-Jurga S, Hebanowska A, Turyn J, Swierczynski J, Sledzinski T, Stelmanska E (2020) The pathophysiological role of CoA. Int J Mol Sci 21:9057. https://doi.org/10.3390/ijms21239057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bates CJ (2005) Pantothenic acid. In: Caballero B (ed) Encyclopedia of human nutrition, 2nd edn. Elsevier, Amsterdam

    Google Scholar 

  58. Tahiliani AG, Beinlich CJ (1991) Pantothenic acid in health and disease. Vitam Horm 46:165–228. https://doi.org/10.1016/s0083-6729(08)60684-6

    Article  CAS  PubMed  Google Scholar 

  59. Ma T, Liu T, Xie P, Jiang S, Yi W, Dai P, Guo X (2020) UPLC-MS-based urine nontargeted metabolic profiling identifies dysregulation of pantothenate and CoA biosynthesis pathway in diabetic kidney disease. Life Sci 258:118160. https://doi.org/10.1016/j.lfs.2020.118160

    Article  CAS  PubMed  Google Scholar 

  60. Smith SM, Abrams SA, Davis-Street JE, Heer M, O’Brien KO, Wastney ME, Zwart SR (2014) Fifty years of human space travel: implications for bone and calcium research. Annu Rev Nutr 34:377–400. https://doi.org/10.1146/annurev-nutr-071813-105440

    Article  CAS  PubMed  Google Scholar 

  61. Suzuki A, Minamide M, Iwaya C, Ogata K, Iwata J (2020) Role of metabolism in bone development and homeostasis. Int J Mol Sci 21:8992. https://doi.org/10.3390/ijms21238992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Buckey J (2006) Bone loss: managing calcium and bone loss in space, vol 5. Oxford University Press, New York, NY

    Google Scholar 

  63. Michel EL, Rummel JA, Sawin CF, Buderer MC, Lem JD (1974) Results of skylab medical experiment M171: metabolic activity. National Aeronautics and Space Administration, Washington DC

    Google Scholar 

  64. Leach CS, Alfrey CP, Suki WN, Leonard JI, Rambaut PC, Inners LD, Smith SM, Lane HW, Krauhs JM (1996) Regulation of body fluid compartments during short-term spaceflight. J App Physiol 81:105–116. https://doi.org/10.1152/jappl.1996.81.1.105

    Article  CAS  Google Scholar 

  65. Stahn AC, Werner A, Opatz O, Maggioni MA, Steinach M, von Ahlefeld VW, Moore A, Crucian BE, Smith SM, Zwart SR, Schlabs T, Mendt S, Trippel T, Koralewski E, Koch J, Choukèr A, Reitz G, Shang P, Röcker L, Kirsch KA, Gunga H-C (2017) Increased core body temperature in astronauts during long-duration space missions. Sci Rep 7:16180. https://doi.org/10.1038/s41598-017-15560-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Crucian BE, Zwart SR, Mehta S, Uchakin P, Quiriarte HD, Pierson D, Sams CF, Smith SM (2014) Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight. J Interferon Cytokine Res 34:778–786. https://doi.org/10.1089/jir.2013.0129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Krieger SS, Zwart SR, Mehta S, Wu H, Simpson RJ, Smith SM, Crucian B (2021) Alterations in saliva and plasma cytokine concentrations during long-duration spaceflight. Front Immun 12:725748. https://doi.org/10.3389/fimmu.2021.725748

    Article  CAS  Google Scholar 

  68. Stegink LD (1984) Aspartate and glutamate metabolism. Aspartame physiology and biochemistry. Marcel Dekker, New York, pp 47–76

    Google Scholar 

  69. Nikiforova VJ, Giesbertz P, Wiemer J, Bethan B, Looser R, Liebenberg V, Ruiz Noppinger P, Daniel H, Rein D (2014) Glyoxylate, a new marker metabolite of type 2 diabetes. J Diabetes Res. https://doi.org/10.1155/2014/685204

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lopez M, Mohiuddin S (2020) Biochemistry, essential amino acids. StatPearls Publishing, Treasure Island (FL)

    Google Scholar 

  71. Li X, Chung ACK, Li S, Wu L, Xu J, Yu J, Wong C, Cai Z (2017) LC-MS-based metabolomics revealed SLC25A22 as an essential regulator of aspartate-derived amino acids and polyamines in KRAS-mutant colorectal cancer. Oncotarget 8:101333–101344. https://doi.org/10.18632/oncotarget.21093

    Article  PubMed  PubMed Central  Google Scholar 

  72. Benowitz NL, Jacob P III, Mayan H, Denaro C (1995) Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharm Therap 58:684–691. https://doi.org/10.1016/0009-9236(95)90025-X

    Article  CAS  PubMed  Google Scholar 

  73. Ibba M, Söll D (2000) Aminoacyl-tRNA synthesis. Ann Rev Biochem 69:617–650. https://doi.org/10.1146/annurev.biochem.69.1.617

    Article  CAS  PubMed  Google Scholar 

  74. Garlick PJ (2005) The role of leucine in the regulation of protein metabolism. J Nutr 135:1553S-1556S. https://doi.org/10.1093/jn/135.6.1553S

    Article  CAS  PubMed  Google Scholar 

  75. Pérez-Sala D, Parrilla R, Ayuso MS (1987) Key role of l-alanine in the control of hepatic protein synthesis. Biochem J 241:491–498. https://doi.org/10.1042/bj2410491

    Article  PubMed  PubMed Central  Google Scholar 

  76. Amorim Franco TM, Blanchard JS (2017) Bacterial branched-chain amino acid biosynthesis: structures, mechanisms, and drugability. Biochemistry 56:5849–5865. https://doi.org/10.1021/acs.biochem.7b00849

    Article  CAS  PubMed  Google Scholar 

  77. Pue N, Guddat L (2014) Acetohydroxyacid synthase: a target for antimicrobial drug discovery. Curr Pharm Des 20:740–753. https://doi.org/10.2174/13816128113199990009

    Article  CAS  PubMed  Google Scholar 

  78. Zhang S, Zeng X, Ren M, Mao X, Qiao S (2017) Novel metabolic and physiological functions of branched chain amino acids: a review. J Anim Sci 8:1–12. https://doi.org/10.1186/s40104-016-0139-z

    Article  CAS  Google Scholar 

  79. Holeček M (2018) Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab 15:33. https://doi.org/10.1186/s12986-018-0271-1

    Article  CAS  Google Scholar 

  80. Blomstrand E, Eliasson J, Karlsson HK, Köhnke R (2006) Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr 136:269S-273S. https://doi.org/10.1093/jn/136.1.269S

    Article  CAS  PubMed  Google Scholar 

  81. Heer M, De Santo NG, Cirillo M, Drummer C (2001) Body mass changes, energy, and protein metabolism in space. Am J Kidney Dis 38:691–695. https://doi.org/10.1053/ajkd.2001.27767

    Article  CAS  PubMed  Google Scholar 

  82. Davis JM, Alderson NL, Welsh RS (2000) Serotonin and central nervous system fatigue: nutritional considerations. Am J of Clin Nutr 72:573S-578S. https://doi.org/10.1093/ajcn/72.2.573S

    Article  CAS  Google Scholar 

  83. Hutson SM, Sweatt AJ, LaNoue KF (2005) Branched-chain amino acid metabolism: implications for establishing safe intakes. J Nutr 135:1557S-1564S. https://doi.org/10.1093/jn/135.6.1557S

    Article  CAS  PubMed  Google Scholar 

  84. Platell C, Kong S-E, McCauley R, Hall JC (2000) Branched-chain amino acids. J Gastroenterol 15:706–717. https://doi.org/10.1046/j.1440-1746.2000.02205.x

    Article  CAS  Google Scholar 

  85. Martínez-Reyes I, Chandel NS (2020) Mitochondrial TCA cycle metabolites control physiology and disease. Nature Comm 11:102. https://doi.org/10.1038/s41467-019-13668-3

    Article  CAS  Google Scholar 

  86. Zheng S, Yu M, Lu X, Huo T, Ge L, Yang J, Wu C, Li F (2010) Urinary metabonomic study on biochemical changes in chronic unpredictable mild stress model of depression. Clin Chim Acta 411:204–209. https://doi.org/10.1016/j.scitotenv.2017.02.149

    Article  CAS  PubMed  Google Scholar 

  87. Olsen T, Øvrebø B, Haj-Yasein N, Lee S, Svendsen K, Hjorth M, Bastani NE, Norheim F, Drevon CA, Refsum H, Vinknes KJ (2020) Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study. J Translat Med 18:122. https://doi.org/10.1186/s12967-020-02288-x

    Article  CAS  Google Scholar 

  88. Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, Arrazola MS, Retamales RM, Bunout D, Hirsch S, Inestrosa NC (2015) Is L-methionine a trigger factor for Alzheimer’s-like neurodegeneration?: changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Mol Neurodegen 10:62. https://doi.org/10.1186/s13024-015-0057-0

    Article  CAS  Google Scholar 

  89. Prentki M, Madiraju SRM (2008) Glycerolipid metabolism and signaling in health and disease. Endocrine Rev 29:647–676. https://doi.org/10.1210/er.2008-0007

    Article  CAS  Google Scholar 

  90. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G (2014) Serine and glycine metabolism in cancer. Biochem Sci 39:191–198. https://doi.org/10.1016/j.tibs.2014.02.004

    Article  CAS  Google Scholar 

  91. Geeraerts SL, Heylen E, De Keersmaecker K, Kampen KR (2021) The ins and outs of serine and glycine metabolism in cancer. Nature Metab 3:131–141. https://doi.org/10.1038/s42255-020-00329-9

    Article  CAS  Google Scholar 

  92. Lieu EL, Nguyen T, Rhyne S, Kim J (2020) Amino acids in cancer. Exp Mol Med 52:15–30. https://doi.org/10.1038/s12276-020-0375-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cronan J, Laporte JED (2005) Tricarboxylic acid cycle and glyoxylate bypass. EcoSal Plus. https://doi.org/10.1128/ecosalplus.3.5.2

    Article  PubMed  Google Scholar 

  94. Bonafé M, Ceccarelli C, Farabegoli F, Santini D, Taffurelli M, Barbi C, Marzi E, Trapassi C, Stroci G, Olivieri F, Fraceschi C (2003) Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients. Clin Cancer Res 9:4860–4864

    PubMed  Google Scholar 

  95. Phang J (2012) The proline regulatory axis and cancer. Front Oncol 2:60. https://doi.org/10.3389/fonc.2012.00060

    Article  PubMed  PubMed Central  Google Scholar 

  96. Phang JM (2019) Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxid Red Signal 30:635–649. https://doi.org/10.1089/ars.2017.7350

    Article  CAS  Google Scholar 

  97. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Rhoads JM, Satterfield MC, Smith SB, Spencer TE, Yin Y (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168. https://doi.org/10.1007/s00726-008-0210-y

    Article  CAS  PubMed  Google Scholar 

  98. Shao W-H, Fan S-H, Lei Y, Yao G-E, Chen J-J, Zhou J, Xu H-B, Liu H-P, Wu B, Zheng P, Fang L, Xie P (2013) Metabolomic identification of molecular changes associated with stress resilience in the chronic mild stress rat model of depression. Metabolomics 9:433–443. https://doi.org/10.1007/s11306-012-0460-2

    Article  CAS  Google Scholar 

  99. Meerman M, Bracco Gartner TCL, Buikema JW, Wu SM, Siddiqi S, Bouten CVC, Grande-Allen KJ, Suyker WJL, Hjortnaes J (2021) Myocardial disease and long-distance space travel: solving the radiation problem. Front Cardiovasc Med 8:27. https://doi.org/10.3389/fcvm.2021.631985

    Article  CAS  Google Scholar 

  100. Uruno A, Saigusa D, Suzuki T, Yumoto A, Nakamura T, Matsukawa N, Yamazaki T, Saito R, Taguchi K, Suzuki M, Suzuki N, Otsuki A, Katsuoka F, Hishinuma E, Okada R, Koshiba S, Tomioka Y, Shimizu R, Shirakawa M, Kensler TW, Shiba D, Yamamoto M (2021) Nrf2 plays a critical role in the metabolic response during and after spaceflight. Comm Bio 4:1381. https://doi.org/10.1038/s42003-021-02904-6

    Article  CAS  Google Scholar 

  101. Jena N (2012) DNA damage by reactive species: mechanisms, mutation and repair. J Biosci 37:503–517. https://doi.org/10.1007/s12038-012-9218-2

    Article  CAS  PubMed  Google Scholar 

  102. Luo X, Cheng C, Tan Z, Li N, Tang M, Yang L, Cao Y (2017) Emerging roles of lipid metabolism in cancer metastasis. Mol Cancer 16:76. https://doi.org/10.1186/s12943-017-0646-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Balder Y, Vignoli A, Tenori L, Luchinat C, Saccenti E (2021) Exploration of blood lipoprotein and lipid fraction profiles in healthy subjects through integrated univariate, multivariate, and network analysis reveals association of lipase activity and cholesterol esterification with sex and age. Metabolites 11:326. https://doi.org/10.3390/metabo11050326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Smith SM, Wastney ME, O’Brien KO, Morukov BV, Larina IM, Abrams SA, Davis-Street JE, Oganov V, Shackelford LC (2005) Bone markers, calcium metabolism, and calcium kinetics during extended-duration space flight on the Mir space station. J Bone Miner Res 20:208–218. https://doi.org/10.1359/jbmr.041105

    Article  CAS  PubMed  Google Scholar 

  105. Sibonga JD, Evans HJ, Sung HG, Spector ER, Lang TF, Oganov VS, Bakulin AV, Shackelford LC, LeBlanc AD (2007) Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function. Bone 41:973–978. https://doi.org/10.1016/j.bone.2007.08.022

    Article  CAS  PubMed  Google Scholar 

  106. Cancedda R (2001) The skeletal system. ESA Publications Division Noordwijk, Paris France

    Google Scholar 

  107. Suzuki N, Iwamura Y, Nakai T, Kato K, Otsuki A, Uruno A, Saigusa D, Taguchi K, Suzuki M, Shiizu R, Yumoto A, Okada R, Shirakawa M, Shiba D, Takashi S, Suzuki T, Yamamoto M (2022) Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel. Kidney Int 101:92–105. https://doi.org/10.1016/j.kint.2021.09.031

    Article  CAS  PubMed  Google Scholar 

  108. Shackelford LC (2008) Musculoskeletal response to space flight. Springer Science & Business Media, New York

    Book  Google Scholar 

  109. Cann CE (1997) Response of the skeletal system to spaceflight, vol 1. Krieger Publishing Company, Malabar, FL

    Google Scholar 

  110. Buckey J (2006) Effect of spaceflight on the cardiovascular system. Oxford University Press, New York, NY

    Google Scholar 

  111. Goel N, Bale TL, Epperson CN, Kornstein SG, Leon GR, Palinkas LA, Stuster JW, Dinges DF (2014) Effects of sex and gender on adaptation to space: behavioral health. J Women’s Health 23:975–986. https://doi.org/10.1089/jwh.2014.4911

    Article  Google Scholar 

  112. Verma R, Balhara YPS, Gupta CS (2011) Gender differences in stress response: Role of developmental and biological determinants. Ind Psychiatry J 20:4–10. https://doi.org/10.4103/0972-6748.98407

    Article  PubMed  PubMed Central  Google Scholar 

  113. Smith SM, Heer MA, Shackelford LC, Sibonga JD, Ploutz-Snyder L, Zwart SR (2012) Benefits for bone from resistance exercise and nutrition in long- duration spaceflight: evidence from biochemistry and densitometry. J Bone Miner Res 27:1896–1906. https://doi.org/10.1002/jbmr.1647

    Article  CAS  PubMed  Google Scholar 

  114. Boonyaratanakornkit JB, Cogoli A, Li CF, Schopper T, Pippia P, Galleri G, Meloni MA, Hughes-Fulford M (2005) Key gravity-sensitive signaling pathways drive T-cell activation. FASEB J 19:2020–2022. https://doi.org/10.1096/fj.05-3778fje

    Article  CAS  PubMed  Google Scholar 

  115. Mao X, Zeng X, Qiao S, Wu G, Li D (2011) Specific roles of threonine in intestinal mucosal integrity and barrier function. Front Biosci 3:200

    Google Scholar 

  116. Hawkins W, Zieglschmid J (1975) Clinical aspects of crew health. National Aeronautics and Space Administration, Washington DC

    Google Scholar 

  117. Kimzey SL (1977) Hematology and immunology studies. Scientific and Technical Information Office, National Aeronautics and Space Association, Washington DC

    Google Scholar 

  118. Crucian B (2008) Risk of crew adverse health event due to altered immune response. National Aeronautics and Space Administration, Washington DC

    Google Scholar 

  119. Wishart DS (2008) Quantitative metabolomics using NMR. Trends Analyt Chem 27:228–237. https://doi.org/10.1016/j.trac.2007.12.001

    Article  CAS  Google Scholar 

  120. Chen Z, Stanbouly S, Nishiyama NC, Chen X, Delp MD, Qiu H, Mao XW, Wang C (2021) Spaceflight decelerates the epigenetic clock orchestrated with a global alteration in DNA methylome and transcriptome in the mouse retina. Precis Clin Med 4:93–108. https://doi.org/10.1093/pcmedi/pbab012

    Article  PubMed  PubMed Central  Google Scholar 

  121. Mulligan CJ (2016) Early environments, stress, and the epigenetics of human health. Annu Rev Anthropol 45:233–249. https://doi.org/10.1146/annurev-anthro-102215-095954

    Article  Google Scholar 

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Acknowledgements

We thank the NASA JSC Nutritional Biochemistry Lab for their efforts in coordination of study protocols and sample collection, processing, and management. We are grateful to the NASA Human Research Program’s Human Health Countermeasures Element for their support and funding of the underlying projects reported herein. We acknowledge Braeden Heninger, Mat Williamson, Cole Pawlenchuk, Ben Wright, Clay Powelson, and Shae Hilderman for their assistance in sample preparation. We also thank the University of Lethbridge Magnetic Resonance Facility (Lethbridge, AB, Canada) for providing access to and training on the Bruker 700 MHz NMR instrument, and Michael Opyr for assistance with NMR data collection and processing methods used to complete this study. We are grateful to Jyote Boora for his contribution in initiating this collaboration.

Funding

This work was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC), Discovery Grant # 05519 to G.M., an Alberta Innovates (AI) Summer Research Studentship to J.S., and a Health Research Accelerator Fund grant from the University of Lethbridge Research Services Office to G.M. and T.M. The primary studies were funded by the Human Health Countermeasures Element of the NASA Human Research Program. Dr. Heer’s support was provided in part by grant WB 0931 from the German Aerospace Center (DLR), Germany.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, EP1274 Exploration Place, University of Lethbridge, Lethbridge, AB, T1K 3M4, Canada

    Julia E. Stroud & Tony Montina

  2. Southern Alberta Genome Sciences Centre, University of Lethbridge, 4401 University Drive, Lethbridge, AB, Canada

    Julia E. Stroud, Michael S. Gale, Tony Montina & Gerlinde A. S. Metz

  3. Department of Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, Canada

    Michael S. Gale & Gerlinde A. S. Metz

  4. Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K 3M4, Canada

    Michael S. Gale & Gerlinde A. S. Metz

  5. University of Texas Medical Branch, Galveston, TX, USA

    Sara R. Zwart

  6. IU International University of Applied Sciences, University of Bonn, Bonn, Germany

    Martina Heer

  7. Biomedical Research and Environmental Sciences Division, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, 77058, USA

    Scott M. Smith

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Contributions

SZ, SS, MH, TM, and GM designed the study. SZ and SS assisted with sample collection and coordinated data analysis. JS, MG, and TM prepared the samples for 1H NMR and analysed the data. JS, MG, SS, TM, and GM contributed to writing the manuscript. All authors have read and approved the final version of the manuscript.

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Correspondence to Scott M. Smith, Tony Montina or Gerlinde A. S. Metz.

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None of the authors declare any competing interests.

Ethics approval and consent to participate

Participants provided written informed consent prior to sample collection, as well as for the extended analyses reported herein. Approval for this study was granted by Human Participant Research Committee at the University of Lethbridge (# 2021-107), the National Aeronautics and Space Administration (NASA) Johnson Space Center Institutional Review Board (# 0225, 0326, 0797), the Japanese Aerospace Exploration Agency, and the European Space Agency Medical Boards.

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Stroud, J.E., Gale, M.S., Zwart, S.R. et al. Longitudinal metabolomic profiles reveal sex-specific adjustments to long-duration spaceflight and return to Earth. Cell. Mol. Life Sci. 79, 578 (2022). https://doi.org/10.1007/s00018-022-04566-x

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