{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T06:10:10Z","timestamp":1771740610084,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"publisher","award":["NPRP11S\u20100122\u2010180359"],"award-info":[{"award-number":["NPRP11S\u20100122\u2010180359"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018\u2010094211\u2010B\u2010100"],"award-info":[{"award-number":["RTI2018\u2010094211\u2010B\u2010100"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2021\u2010122802OB\u2010100"],"award-info":[{"award-number":["PID2021\u2010122802OB\u2010100"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The neutral amino acid transporter <jats:italic>SLC7A8<\/jats:italic> (LAT2) has been described as a key regulator of metabolic adaptation. LAT2 mutations in human populations have been linked to the early onset of age\u2010related hearing loss and cataract growth. As LAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of <jats:italic>skeletal muscle<\/jats:italic> amino acid flux and metabolic adaptation to fasting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type (WT) and LAT2 knock\u2010out (LAT2KO) mice were exposed to short\u2010 and long\u2010periods of fasting (16 and 48\u2009h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histology was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer\u2010associated cachexia, streptozocin\u2010induced Type\u20101 diabetes, and ageing models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, <jats:italic>p<\/jats:italic>\u2009=\u20090.02), with a greater reduction in fat mass (0.5\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.013) and a higher relative retention of muscle mass (1.3\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.0003) compared with WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3\u2010fold, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), accompanied by a reduction in skeletal muscle proteolysis during fasting (0.61\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.0004) primarily due to decreased proteasomal and autophagic activity (0.45\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.016 and 0.7\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.002, respectively). Ex\u00a0vivo incubation of LAT2KO muscle with rapamycin recovered proteolysis function, demonstrating a mTORC1\u2010dependent pathway. Decreased proteolysis in LAT2KO animals was associated with increased mTORC1 translocation to the lysosome (mTORC1\u2010Lamp1 colocalization in fasted LAT2KO muscles was 1.23\u2010fold, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Of the three muscle loss models tested, differences were observed only during ageing. Young LAT2KO mice (3\u2009M) exhibited muscle tone and MurF1 expression levels comparable to those of older WT mice (12\u2009M) (0.44\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.02 and 0.48\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.04, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>LAT2 has a critical role in regulating Gln efflux from skeletal muscle. The absence of LAT2 led to elevated intracellular Gln levels, impairing muscle proteolysis by inducing mTORC1 recruitment to the lysosome. Further, chronic Gln accumulation and decreased proteolysis were found to induce the early onset of an age\u2010related muscle phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13847","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T09:39:51Z","timestamp":1750671591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting\u2010Induced Proteolysis"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-3229","authenticated-orcid":false,"given":"Meritxell","family":"Espino\u2010Guarch","sequence":"first","affiliation":[{"name":"Laboratory of Immunoregulation, Research Department, Sidra Medicine  Doha 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M.Kolaczkowski B. A.Goodson V. M.Vazquez J.Jia A. Q.Bhat T. H.Kim andJ.Pu \u201cSynergistic Role of Amino Acids in Enhancing mTOR Activation Through Lysosome Positioning \u201d bioRxiv (2024). 2024.10.12.618047.https:\/\/doi.org\/10.1101\/2024.10.12.618047.","DOI":"10.1101\/2024.10.12.618047"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1966.210.5.1101"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.01.004"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.009"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.12.035"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.08.021"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.024"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.019"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI135124"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology11020311"}],"updated-by":[{"DOI":"10.1002\/jcsm.70015","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,7,27]],"date-time":"2025-07-27T00:00:00Z","timestamp":1753574400000}}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13847","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T10:24:05Z","timestamp":1750847045000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.13847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/jcsm.13847"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.13847","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1002\/jcsm.70015","asserted-by":"object"}]},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]},"assertion":[{"value":"2024-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13847"}}