{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:47:24Z","timestamp":1791233244503,"version":"4.1.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"36","funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Grant-in-Aid for Challenging Research","award":["25K22769"],"award-info":[{"award-number":["25K22769"]}]},{"name":"JST FOREST Program","award":["JPMJFR234H"],"award-info":[{"award-number":["JPMJFR234H"]}]},{"name":"The Japan Health Research Promotion Bureau","award":["2023-Young-07"],"award-info":[{"award-number":["2023-Young-07"]}]},{"name":"The Japan Health Research Promotion Bureau","award":["2024-B-07"],"award-info":[{"award-number":["2024-B-07"]}]},{"name":"THE HORI SCIENCE AND ARTS FOUNDATION"},{"name":"the Research and Development Grants for Longevity Science","award":["JP25dk0110052"],"award-info":[{"award-number":["JP25dk0110052"]}]},{"name":"the Research Fund for Longevity Sciences from the NCGG","award":["22-30"],"award-info":[{"award-number":["22-30"]}]},{"name":"the Research Fund for Longevity Sciences from the NCGG","award":["25-26"],"award-info":[{"award-number":["25-26"]}]},{"name":"the Naito Foundation Next Generation Support research grant"},{"name":"the Advanced Research & Development Programs for Medical Innovation","award":["JP25gm2110003"],"award-info":[{"award-number":["JP25gm2110003"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle. Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1\u03b1 improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1\u03b1 in the liver as a pharmacological target for sarcopenia.<\/jats:p>","DOI":"10.1126\/sciadv.aeb4011","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:58:46Z","timestamp":1788544726000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0363-5874","authenticated-orcid":true,"given":"Takahiro","family":"Eguchi","sequence":"first","affiliation":[{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-3846","authenticated-orcid":true,"given":"Nozomi","family":"Hayashiji","sequence":"additional","affiliation":[{"name":"Juntendo Advanced Research Institute for Health Science, Juntendo University Graduate School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8956-9241","authenticated-orcid":true,"given":"Sho","family":"Tabata","sequence":"additional","affiliation":[{"name":"Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan."},{"name":"Shonai Regional Industry Promotion Center, Tsuruoka, Japan."},{"name":"Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kabetani","sequence":"additional","affiliation":[{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9579-0727","authenticated-orcid":true,"given":"Yasunori","family":"Shintani","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8181-6241","authenticated-orcid":true,"given":"Hideki","family":"Makinoshima","sequence":"additional","affiliation":[{"name":"Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan."},{"name":"Shonai Regional Industry Promotion Center, Tsuruoka, Japan."},{"name":"Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-8494","authenticated-orcid":true,"given":"Naoki","family":"Ito","sequence":"additional","affiliation":[{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1462"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2014.00192"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa016"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.7861\/clinmed.2020-0089"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00373.2020"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/61.1.72"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13694-1"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology10010031"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.04.003"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41514-025-00192-6"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0161-5"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.11.037"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.10.020"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19092804"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.4161\/chan.24583"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3019"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2011.10.005"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2024_567"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-019-0668-y"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ado3022"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2005.09.004"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25185-3"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.489674"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw943"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01151-3"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.09.001"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1309483"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111131"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1030514"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2019-0010"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22168-2"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn4508"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3430281"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2021.02.012"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.12.009"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14224"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.07.027"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2014.tb00548.x"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.150917"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00248-17"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1515872112"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2019.09.118"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.7.4685"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-2-8"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00797-8"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70188"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12995"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/61.10.1059"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01011-0"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00312-8"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjfa.2024.100004"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000026114"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add3216"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004240100528"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813599"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000318"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1177\/1091581817737232"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1039\/B714176A"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1039\/c0mb00141d"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-009-0178-y"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz209"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/bit.10393"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41514-023-00098-1"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08232-2"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeb4011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:00:19Z","timestamp":1788544819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeb4011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":65,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,4]]}},"alternative-id":["10.1126\/sciadv.aeb4011"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeb4011","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"assertion":[{"value":"2025-08-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb4011"}}