{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:35:05Z","timestamp":1791614105053,"version":"4.3.4"},"reference-count":51,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100015728","name":"Clinical Science Research and Development","doi-asserted-by":"publisher","award":["IK2CX002114"],"award-info":[{"award-number":["IK2CX002114"]}],"id":[{"id":"10.13039\/100015728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Intramuscular hydrogen ion (H<jats:sup>+<\/jats:sup>) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue <jats:italic>in vivo<\/jats:italic>. Ten recreationally active, healthy men (27\u00a0\u00b1\u00a05\u00a0years; 180\u00a0\u00b1\u00a04\u00a0cm; 76\u00a0\u00b1\u00a010\u00a0kg) performed two consecutive intermittent isometric single\u2010leg knee\u2010extensor trials (60 maximal voluntary contractions; 3\u00a0s contraction, 2\u00a0s relaxation) interspersed with 5\u00a0min of rest. Phosphorus magnetic resonance spectroscopy (<jats:sup>31<\/jats:sup>P\u2010MRS) was used to continuously quantify intramuscular [H<jats:sup>+<\/jats:sup>] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (<jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub>) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> and VA from baseline were used to determine peripheral and central fatigue, respectively. <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> was strongly related to both [H<jats:sup>+<\/jats:sup>] (\u03b2 coefficient: \u22120.9, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and [Pi] (\u22121.1, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) across trials. There was an effect of trial on the relationship between <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> and [H<jats:sup>+<\/jats:sup>] (\u22120.5, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), but not <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> and [Pi] (0.0, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H<jats:sup>+<\/jats:sup>] in Trial 1 <jats:italic>vs<\/jats:italic>. Trial 2. VA was related to [H<jats:sup>+<\/jats:sup>] (\u22120.3, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), but not [Pi] (\u22120.2, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.243), across trials and there was no effect of trial (\u22120.1, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III\/IV muscle afferents in the interstitial space,\u00a0as a contributor to central fatigue during exercise.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15098-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee\u2010extension trials interspersed with 5\u00a0min of rest.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Concomitant measurements of intramuscular hydrogen (H<jats:sup>+<\/jats:sup>) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch\u2010force (<jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub>) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (<jats:sup>31<\/jats:sup>P\u2010MRS) and electrical femoral nerve stimulations.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Although [Pi] fully recovered prior to the onset of the second trial, [H<jats:sup>+<\/jats:sup>] did not.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> was strongly related to both [H<jats:sup>+<\/jats:sup>] and [Pi] across both trials. However, the relationship between <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> and [H<jats:sup>+<\/jats:sup>] shifted leftward from the first to the second trial, whereas the relationship between <jats:italic>Q<\/jats:italic><jats:sub>tw<\/jats:sub> and [Pi] remained unaltered. VA was related to [H<jats:sup>+<\/jats:sup>], but not [Pi], across both trials.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These <jats:italic>in vivo<\/jats:italic> findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III\/IV muscle afferents,\u00a0as a contributor to central fatigue.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283036","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T13:01:45Z","timestamp":1653051705000},"page":"3069-3081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["On the role of skeletal muscle acidosis and inorganic phosphates as determinants of central and peripheral fatigue: A <sup>31<\/sup>P\u2010MRS study"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6993-5723","authenticated-orcid":false,"given":"Thomas J.","family":"Hureau","sequence":"first","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"},{"name":"University of Strasbourg Faculty of Sport Sciences, UR 3072: Mitochondria Oxidative Stress and Muscular Protection Laboratory  Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7388-2214","authenticated-orcid":false,"given":"Ryan M.","family":"Broxterman","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center  Salt Lake City UT VAMC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-8498","authenticated-orcid":false,"given":"Joshua C.","family":"Weavil","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center  Salt Lake City UT VAMC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0580-6866","authenticated-orcid":false,"given":"Matthew T.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center  Salt Lake City UT VAMC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5029-2457","authenticated-orcid":false,"given":"Gwenael","family":"Layec","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Amann","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center  Salt Lake City UT VAMC USA"},{"name":"Department of Anesthesiology University of Utah  Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1991.260.4.C805"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2007"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.163303"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1249\/JES.0000000000000233"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272283"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01093.2016"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0b013e3181f9b1c4"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1988.sp016909"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/274861a0"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.09.046"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880160115"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-009-0713-8"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0000000000001043"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018605605757"},{"key":"e_1_2_6_16_1","volume-title":"Nuclear magnetic resonance and its applications to living systems","author":"Gadian D. 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