{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:49:03Z","timestamp":1790671743563,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T00:00:00Z","timestamp":1553817600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010115","name":"R\u00e9gion Auvergne-Rh\u00f4ne-Alpes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010115","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":[[2019,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sarcopenia is the loss of muscle mass\/function that occurs during the aging process. The links between mechanistic target of rapamycin (mTOR) activity and muscle development are largely documented, but the role of its downstream targets in the development of sarcopenia is poorly understood. Eukaryotic initiation factor 4E\u2010binding proteins (4E\u2010BPs) are targets of mTOR that repress mRNA translation initiation and are involved in the control of several physiological processes. However, their role in skeletal muscle is still poorly understood. The goal of this study was to assess how loss of 4E\u2010BP1 and 4E\u2010BP2 expression impacts skeletal muscle function and homeostasis in aged mice and to characterize the associated metabolic changes by metabolomic and lipidomic profiling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010four\u2010month\u2010old wild\u2010type and whole body 4E\u2010BP1\/4E\u2010BP2 double knockout (DKO) mice were used to measure muscle mass and function. Protein homeostasis was measured <jats:italic>ex vivo<\/jats:italic> in extensor digitorum longus by incorporation of <jats:sc>l<\/jats:sc>\u2010[U\u2010<jats:sup>14<\/jats:sup>C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The 4E\u2010BP1\/2 DKO mice exhibited an increase in muscle mass that was associated with increased grip strength (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Protein synthesis was higher under both basal (+102%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and stimulated conditions (+65%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in DKO skeletal muscle. Metabolomic and complex lipid analysis of skeletal muscle revealed robust differences pertaining to amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In particular, levels of most free amino acids were lower within the 4E\u2010BP1\/2 DKO muscle. Interestingly, although glucose levels were unchanged, differences were observed in the isobaric compound maltitol\/lactitol (33\u2010fold increase, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and in several additional carbohydrate compounds. 4E\u2010BP1\/2 depletion also resulted in accumulation of medium\u2010chain acylcarnitines and a 20% lower C2\/C0 acylcarnitine ratio (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) indicative of reduced \u03b2\u2010oxidation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, these findings demonstrate that deletion of 4E\u2010BPs is associated with perturbed energy metabolism in skeletal muscle and could have beneficial effects on skeletal muscle mass and function in aging mice. They also identify 4E\u2010BPs as potential targets for the treatment of sarcopenia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12412","type":"journal-article","created":{"date-parts":[[2019,3,30]],"date-time":"2019-03-30T04:10:29Z","timestamp":1553919029000},"page":"696-709","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["4E\u2010BP1 and 4E\u2010BP2 double knockout mice are protected from aging\u2010associated sarcopenia"],"prefix":"10.1002","volume":"10","author":[{"given":"Olivier","family":"Le Bacquer","sequence":"first","affiliation":[{"name":"INRA, UMR1019 Universit\u00e9 Clermont Auvergne, UNH, Unit\u00e9 de Nutrition Humaine  CRNH Auvergne Clermont\u2010Ferrand France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristell","family":"Combe","sequence":"additional","affiliation":[{"name":"INRA, UMR1019 Universit\u00e9 Clermont Auvergne, UNH, Unit\u00e9 de Nutrition Humaine  CRNH Auvergne Clermont\u2010Ferrand France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Patrac","sequence":"additional","affiliation":[{"name":"INRA, UMR1019 Universit\u00e9 Clermont Auvergne, UNH, Unit\u00e9 de Nutrition Humaine  CRNH Auvergne Clermont\u2010Ferrand France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Ingram","sequence":"additional","affiliation":[{"name":"Metabolon Inc.  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