{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T23:21:48Z","timestamp":1793575308363,"version":"4.5.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:00:00Z","timestamp":1625875200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:00:00Z","timestamp":1625875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R03-AG067949"],"award-info":[{"award-number":["R03-AG067949"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R21-AR076663"],"award-info":[{"award-number":["R21-AR076663"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000654","name":"Marie Curie","doi-asserted-by":"publisher","award":["PIOF-GA-2013-629981"],"award-info":[{"award-number":["PIOF-GA-2013-629981"]}],"id":[{"id":"10.13039\/501100000654","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and\/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid\/protein homeostatic pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      ,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02528344\">NCT02528344<\/jats:ext-link>\n                      . Registered on 19 August 2015.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-021-02570-3","type":"journal-article","created":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:02:36Z","timestamp":1625875356000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1847-0660","authenticated-orcid":false,"given":"Brian J.","family":"Andonian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Johannemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica J.","family":"Hubal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Pober","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Koss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Bartlett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim M.","family":"Huffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,10]]},"reference":[{"issue":"7","key":"2570_CR1","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1007\/s00421-014-2877-y","volume":"114","author":"AJ Wadley","year":"2014","unstructured":"Wadley AJ, van Zanten JJV, Stavropoulos-Kalinoglou A, Metsios GS, Smith JP, Kitas GD, et al. Three months of moderate-intensity exercise reduced plasma 3-nitrotyrosine in rheumatoid arthritis patients. Eur J Appl Physiol. 2014;114(7):1483\u201392. https:\/\/doi.org\/10.1007\/s00421-014-2877-y.","journal-title":"Eur J Appl Physiol."},{"issue":"3","key":"2570_CR2","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1002\/1529-0131(200103)44:3<515::AID-ANR98>3.0.CO;2-5","volume":"44","author":"A Hakkinen","year":"2001","unstructured":"Hakkinen A, Sokka T, Kotaniemi A, Hannonen P. A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. Arthritis Rheum. 2001;44(3):515\u201322. https:\/\/doi.org\/10.1002\/1529-0131(200103)44:3<515::AID-ANR98>3.0.CO;2-5.","journal-title":"Arthritis Rheum."},{"issue":"11","key":"2570_CR3","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1136\/annrheumdis-2012-202075","volume":"72","author":"A Stavropoulos-Kalinoglou","year":"2013","unstructured":"Stavropoulos-Kalinoglou A, Metsios GS, van Zanten JJV, Nightingale P, Kitas GD, Koutedakis Y. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72(11):1819\u201325. https:\/\/doi.org\/10.1136\/annrheumdis-2012-202075.","journal-title":"Ann Rheum Dis."},{"issue":"8","key":"2570_CR4","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1136\/ard.59.8.615","volume":"59","author":"CH van den Ende","year":"2000","unstructured":"van den Ende CH, Breedveld FC, le Cessie S, Dijkmans BA, de Mug AW, Hazes JM. Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2000;59(8):615\u201321. https:\/\/doi.org\/10.1136\/ard.59.8.615.","journal-title":"Ann Rheum Dis."},{"issue":"1","key":"2570_CR5","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s13075-018-1624-x","volume":"20","author":"DB Bartlett","year":"2018","unstructured":"Bartlett DB, Willis LH, Slentz CA, Hoselton A, Kelly L, Huebner JL, et al. Ten weeks of high-intensity interval walk training is associated with reduced disease activity and improved innate immune function in older adults with rheumatoid arthritis: a pilot study. Arthritis Res Ther. 2018;20(1):127. https:\/\/doi.org\/10.1186\/s13075-018-1624-x.","journal-title":"Arthritis Res Ther."},{"issue":"5","key":"2570_CR6","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/j.jaci.2015.10.035","volume":"137","author":"M Weinhold","year":"2016","unstructured":"Weinhold M, Shimabukuro-Vornhagen A, Franke A, Theurich S, Wahl P, Hallek M, et al. Physical exercise modulates the homeostasis of human regulatory T cells. J Allergy Clin Immunol. 2016;137(5):1607\u201310 e8. https:\/\/doi.org\/10.1016\/j.jaci.2015.10.035.","journal-title":"J Allergy Clin Immunol."},{"key":"2570_CR7","doi-asserted-by":"publisher","unstructured":"Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17(2):e12750. https:\/\/doi.org\/10.1111\/acel.12750. Epub 2018 Mar 8.","DOI":"10.1111\/acel.12750"},{"key":"2570_CR8","doi-asserted-by":"publisher","unstructured":"Severinsen MCK, Pedersen BK. Muscle-Organ crosstalk: the emerging roles of myokines. Endocr Rev. 2020;41(4):594-609. https:\/\/doi.org\/10.1210\/endrev\/bnaa016.","DOI":"10.1210\/endrev\/bnaa016"},{"issue":"4","key":"2570_CR9","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1152\/physrev.90100.2007","volume":"88","author":"BK Pedersen","year":"2008","unstructured":"Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379\u2013406. https:\/\/doi.org\/10.1152\/physrev.90100.2007.","journal-title":"Physiol Rev."},{"issue":"6","key":"2570_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0156460","volume":"11","author":"A Gudiksen","year":"2016","unstructured":"Gudiksen A, Schwartz CL, Bertholdt L, Joensen E, Knudsen JG, Pilegaard H. Lack of skeletal muscle IL-6 affects pyruvate dehydrogenase activity at rest and during prolonged exercise. PLoS One. 2016;11(6):e0156460. https:\/\/doi.org\/10.1371\/journal.pone.0156460.","journal-title":"PLoS One."},{"key":"2570_CR11","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.3389\/fphys.2018.01307","volume":"9","author":"LG Leal","year":"2018","unstructured":"Leal LG, Lopes MA, Batista ML Jr. Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases. Front Physiol. 2018;9:1307. https:\/\/doi.org\/10.3389\/fphys.2018.01307.","journal-title":"Front Physiol."},{"issue":"4","key":"2570_CR12","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/icb.2014.16","volume":"92","author":"M Pal","year":"2014","unstructured":"Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol. 2014;92(4):331\u20139. https:\/\/doi.org\/10.1038\/icb.2014.16.","journal-title":"Immunol Cell Biol."},{"key":"2570_CR13","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.jaut.2012.07.009","volume":"40","author":"JO Jin","year":"2013","unstructured":"Jin JO, Han X, Yu Q. Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. J Autoimmun. 2013;40:28\u201344. https:\/\/doi.org\/10.1016\/j.jaut.2012.07.009.","journal-title":"J Autoimmun."},{"issue":"8","key":"2570_CR14","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1096\/fj.02-0670fje","volume":"17","author":"R Starkie","year":"2003","unstructured":"Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884\u20136. https:\/\/doi.org\/10.1096\/fj.02-0670fje.","journal-title":"FASEB J."},{"issue":"3","key":"2570_CR15","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1097\/BOR.0000000000000697","volume":"32","author":"BJ Andonian","year":"2020","unstructured":"Andonian BJ, Huffman KM. Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities? Curr Opin Rheumatol. 2020;32(3):297\u2013306. https:\/\/doi.org\/10.1097\/BOR.0000000000000697.","journal-title":"Curr Opin Rheumatol."},{"issue":"1","key":"2570_CR16","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13075-016-1215-7","volume":"19","author":"KM Huffman","year":"2017","unstructured":"Huffman KM, Jessee R, Andonian B, Davis BN, Narowski R, Huebner JL, et al. Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability. Arthritis Res Ther. 2017;19(1):12. https:\/\/doi.org\/10.1186\/s13075-016-1215-7.","journal-title":"Arthritis Res Ther."},{"issue":"1","key":"2570_CR17","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1186\/s13075-018-1786-6","volume":"20","author":"BJ Andonian","year":"2018","unstructured":"Andonian BJ, Bartlett DB, Huebner JL, Willis L, Hoselton A, Kraus VB, et al. Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes. Arthritis Res Ther. 2018;20(1):283. https:\/\/doi.org\/10.1186\/s13075-018-1786-6.","journal-title":"Arthritis Res Ther."},{"issue":"6","key":"2570_CR18","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1007\/s00296-018-4028-y","volume":"38","author":"RJ Boutrup","year":"2018","unstructured":"Boutrup RJ, Farup J, Vissing K, Kjaer M, Mikkelsen UR. Skeletal muscle stem cell characteristics and myonuclei content in patients with rheumatoid arthritis: a cross-sectional study. Rheumatol Int. 2018;38(6):1031\u201341. https:\/\/doi.org\/10.1007\/s00296-018-4028-y.","journal-title":"Rheumatol Int."},{"issue":"3","key":"2570_CR19","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/art.1780310302","volume":"31","author":"FC Arnett","year":"1988","unstructured":"Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315\u201324. https:\/\/doi.org\/10.1002\/art.1780310302.","journal-title":"Arthritis Rheum."},{"issue":"1","key":"2570_CR20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1002\/art.1780380107","volume":"38","author":"ML Prevoo","year":"1995","unstructured":"Prevoo ML, van \u2018t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44\u20138. https:\/\/doi.org\/10.1002\/art.1780380107.","journal-title":"Arthritis Rheum."},{"issue":"2","key":"2570_CR21","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3109\/03009742.2014.931456","volume":"44","author":"KM Huffman","year":"2015","unstructured":"Huffman KM, Pieper CF, Hall KS, St Clair EW, Kraus WE. Self-efficacy for exercise, more than disease-related factors, is associated with objectively assessed exercise time and sedentary behaviour in rheumatoid arthritis. Scand J Rheumatol. 2015;44(2):106\u201310. https:\/\/doi.org\/10.3109\/03009742.2014.931456.","journal-title":"Scand J Rheumatol."},{"key":"2570_CR22","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.3389\/fimmu.2019.01475","volume":"10","author":"BJ Andonian","year":"2019","unstructured":"Andonian BJ, Chou CH, Ilkayeva OR, Koves TR, Connelly MA, Kraus WE, et al. Plasma microRNAs in established rheumatoid arthritis relate to adiposity and altered plasma and skeletal muscle cytokine and metabolic profiles. Front Immunol. 2019;10:1475. https:\/\/doi.org\/10.3389\/fimmu.2019.01475.","journal-title":"Front Immunol."},{"issue":"D1","key":"2570_CR23","doi-asserted-by":"publisher","first-page":"D419","DOI":"10.1093\/nar\/gky1038","volume":"47","author":"H Mi","year":"2019","unstructured":"Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2019;47(D1):D419\u2013D26. https:\/\/doi.org\/10.1093\/nar\/gky1038.","journal-title":"Nucleic Acids Res."},{"issue":"Web Server issu","key":"2570_CR24","doi-asserted-by":"publisher","first-page":"W645","DOI":"10.1093\/nar\/gkl229","volume":"34","author":"PD Thomas","year":"2006","unstructured":"Thomas PD, Kejariwal A, Guo N, Mi H, Campbell MJ, Muruganujan A, et al. Applications for protein sequence-function evolution data: mRNA\/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res. 2006;34(Web Server issue):W645\u201350.","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"2570_CR25","doi-asserted-by":"publisher","first-page":"D498","DOI":"10.1093\/nar\/gkz1031","volume":"48","author":"B Jassal","year":"2020","unstructured":"Jassal B, Matthews L, Viteri G, Gong C, Lorente P, Fabregat A, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020;48(D1):D498\u2013503. https:\/\/doi.org\/10.1093\/nar\/gkz1031.","journal-title":"Nucleic Acids Res."},{"issue":"10","key":"2570_CR26","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.3899\/jrheum.140224","volume":"41","author":"H AbouAssi","year":"2014","unstructured":"AbouAssi H, Tune KN, Gilmore B, Bateman LA, McDaniel G, Muehlbauer M, et al. Adipose depots, not disease-related factors, account for skeletal muscle insulin sensitivity in established and treated rheumatoid arthritis. J Rheumatol. 2014;41(10):1974\u20139. https:\/\/doi.org\/10.3899\/jrheum.140224.","journal-title":"J Rheumatol."},{"key":"2570_CR27","doi-asserted-by":"publisher","unstructured":"Xu J, Jiang C, Cai Y, Guo Y, Wang X, Zhang J, et al. Intervening upregulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6Ksignal in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2020;22(1):200. https:\/\/doi.org\/10.1186\/s13075-020-02296-8.","DOI":"10.1186\/s13075-020-02296-8"},{"issue":"4 Suppl","key":"2570_CR28","doi-asserted-by":"publisher","first-page":"63S","DOI":"10.1177\/014860719001400406","volume":"14","author":"EA Newsholme","year":"1990","unstructured":"Newsholme EA, Parry-Billings M. Properties of glutamine release from muscle and its importance for the immune system. JPEN J Parenter Enteral Nutr. 1990;14(4 Suppl):63S\u20137S. https:\/\/doi.org\/10.1177\/014860719001400406.","journal-title":"JPEN J Parenter Enteral Nutr."},{"issue":"9 Suppl","key":"2570_CR29","doi-asserted-by":"publisher","first-page":"2467S","DOI":"10.1093\/jn\/131.9.2467S","volume":"131","author":"BI Labow","year":"2001","unstructured":"Labow BI, Souba WW, Abcouwer SF. Mechanisms governing the expression of the enzymes of glutamine metabolism--glutaminase and glutamine synthetase. J Nutr. 2001;131(9 Suppl):2467S\u201374S discussion 86S-7S.","journal-title":"J Nutr"},{"issue":"2","key":"2570_CR30","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.cmet.2020.06.010","volume":"32","author":"B Kelly","year":"2020","unstructured":"Kelly B, Pearce EL. Amino assets: how amino acids support immunity. Cell Metab. 2020;32(2):154\u201375. https:\/\/doi.org\/10.1016\/j.cmet.2020.06.010.","journal-title":"Cell Metab."},{"issue":"11","key":"2570_CR31","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1002\/art.41019","volume":"71","author":"M Kono","year":"2019","unstructured":"Kono M, Yoshida N, Maeda K, Suarez-Fueyo A, Kyttaris VC, Tsokos GC. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus-like disease in MRL\/lpr mice and experimental autoimmune encephalomyelitis. Arthritis Rheumatol. 2019;71(11):1869\u201378. https:\/\/doi.org\/10.1002\/art.41019.","journal-title":"Arthritis Rheumatol."},{"issue":"4","key":"2570_CR32","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41422-020-0291-z","volume":"30","author":"EM Palsson-McDermott","year":"2020","unstructured":"Palsson-McDermott EM, O'Neill LAJ. Targeting immunometabolism as an anti-inflammatory strategy. Cell Res. 2020;30(4):300\u201314. https:\/\/doi.org\/10.1038\/s41422-020-0291-z.","journal-title":"Cell Res."},{"key":"2570_CR33","doi-asserted-by":"publisher","unstructured":"Alves A, Bassot A, Bulteau AL, Pirola L, Morio B. Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients. 2019;11(6):1356. https:\/\/doi.org\/10.3390\/nu11061356.","DOI":"10.3390\/nu11061356"},{"issue":"D1","key":"2570_CR34","doi-asserted-by":"publisher","first-page":"D506","DOI":"10.1093\/nar\/gky1049","volume":"47","author":"C UniProt","year":"2019","unstructured":"UniProt C. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47(D1):D506\u2013D15.","journal-title":"Nucleic Acids Res."},{"issue":"7","key":"2570_CR35","doi-asserted-by":"publisher","first-page":"246","DOI":"10.2183\/pjab.84.246","volume":"84","author":"G Kikuchi","year":"2008","unstructured":"Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(7):246\u201363. https:\/\/doi.org\/10.2183\/pjab.84.246.","journal-title":"Proc Jpn Acad Ser B Phys Biol Sci."},{"issue":"10","key":"2570_CR36","doi-asserted-by":"publisher","first-page":"4986","DOI":"10.4049\/jimmunol.170.10.4986","volume":"170","author":"L Quemeneur","year":"2003","unstructured":"Quemeneur L, Gerland LM, Flacher M, Ffrench M, Revillard JP, Genestier L. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol. 2003;170(10):4986\u201395. https:\/\/doi.org\/10.4049\/jimmunol.170.10.4986.","journal-title":"J Immunol."},{"key":"2570_CR37","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.3389\/fimmu.2018.01697","volume":"9","author":"J Yin","year":"2018","unstructured":"Yin J, Ren W, Huang X, Deng J, Li T, Yin Y. Potential mechanisms connecting purine metabolism and cancer therapy. Front Immunol. 2018;9:1697. https:\/\/doi.org\/10.3389\/fimmu.2018.01697.","journal-title":"Front Immunol."},{"key":"2570_CR38","doi-asserted-by":"publisher","unstructured":"Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: metabolism and immune function, supplementation and clinicaltranslation. Nutrients. 2018;10(11):1564. https:\/\/doi.org\/10.3390\/nu10111564.","DOI":"10.3390\/nu10111564"},{"issue":"4","key":"2570_CR39","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s12551-011-0060-9","volume":"3","author":"JM Percival","year":"2011","unstructured":"Percival JM. nNOS regulation of skeletal muscle fatigue and exercise performance. Biophys Rev. 2011;3(4):209\u201317. https:\/\/doi.org\/10.1007\/s12551-011-0060-9.","journal-title":"Biophys Rev."},{"issue":"11","key":"2570_CR40","doi-asserted-by":"publisher","first-page":"7175","DOI":"10.4049\/jimmunol.180.11.7175","volume":"180","author":"H Shime","year":"2008","unstructured":"Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, et al. Tumor-secreted lactic acid promotes IL-23\/IL-17 proinflammatory pathway. J Immunol. 2008;180(11):7175\u201383. https:\/\/doi.org\/10.4049\/jimmunol.180.11.7175.","journal-title":"J Immunol."},{"issue":"6","key":"2570_CR41","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.cmet.2019.10.004","volume":"30","author":"V Pucino","year":"2019","unstructured":"Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K, Pontarini E, et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4(+) T cell metabolic rewiring. Cell Metab. 2019;30(6):1055\u201374 e8. https:\/\/doi.org\/10.1016\/j.cmet.2019.10.004.","journal-title":"Cell Metab."},{"issue":"7","key":"2570_CR42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002202","volume":"13","author":"R Haas","year":"2015","unstructured":"Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015;13(7):e1002202. https:\/\/doi.org\/10.1371\/journal.pbio.1002202.","journal-title":"PLoS Biol."},{"issue":"10","key":"2570_CR43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046571","volume":"7","author":"CJ De Saedeleer","year":"2012","unstructured":"De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7(10):e46571. https:\/\/doi.org\/10.1371\/journal.pone.0046571.","journal-title":"PLoS One."},{"key":"2570_CR44","doi-asserted-by":"publisher","unstructured":"Talreja J, Talwar H, Bauerfeld C, Grossman LI, Zhang K, Tranchida P, et al. HIF-1alpha regulates IL-1beta and IL-17 in sarcoidosis. Elife. 2019;8. https:\/\/doi.org\/10.7554\/eLife.44519.","DOI":"10.7554\/eLife.44519"},{"issue":"12","key":"2570_CR45","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1002\/acr.23550","volume":"70","author":"JF Baker","year":"2018","unstructured":"Baker JF, Mostoufi-Moab S, Long J, Zemel B, Ibrahim S, Taratuta E, et al. Intramuscular fat accumulation and associations with body composition, strength, and physical functioning in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018;70(12):1727\u201334. https:\/\/doi.org\/10.1002\/acr.23550.","journal-title":"Arthritis Care Res (Hoboken)."},{"key":"2570_CR46","doi-asserted-by":"publisher","first-page":"110768","DOI":"10.1016\/j.exger.2019.110768","volume":"129","author":"SS Khoja","year":"2020","unstructured":"Khoja SS, Patterson CG, Goodpaster BH, Delitto A, Piva SR. Skeletal muscle fat in individuals with rheumatoid arthritis compared to healthy adults. Exp Gerontol. 2020;129:110768. https:\/\/doi.org\/10.1016\/j.exger.2019.110768.","journal-title":"Exp Gerontol."}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02570-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-021-02570-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02570-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:02:39Z","timestamp":1625875359000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-021-02570-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,10]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2570"],"URL":"https:\/\/doi.org\/10.1186\/s13075-021-02570-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-322342\/v1","asserted-by":"object"}]},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,10]]},"assertion":[{"value":"8 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All participants gave written informed consent. The study was approved by the Duke University Medical Center Institutional Review Board (IRB no. Pro00064057).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Author DMP is an employee at Phastar Inc. (Cambridge, MA, USA). All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"187"}}