{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:15:16Z","timestamp":1778732116078,"version":"3.51.4"},"reference-count":68,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["(AIRC)\u201020406"],"award-info":[{"award-number":["(AIRC)\u201020406"]}],"id":[{"id":"10.13039\/501100005010","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":[[2022,12]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mammalian target of rapamycin (mTOR) signalling. We wanted to elucidate the functional role of mTOR in muscle contractility. Most loss\u2010of\u2010function studies for mTOR signalling have used the drug rapamycin to inhibit some of the signalling downstream of mTOR. However, given that rapamycin does not inhibit all mTOR signalling completely, we generated a double knockout for mTOR and for the scaffold protein of mTORC1, raptor, in skeletal muscle. We found that double knockout in mice results in a more severe phenotype compared with deletion of raptor or mTOR alone. Indeed, these animals display muscle weakness, increased fibre denervation and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow\u2010twitch fibres and changes in the expression levels of calcium\u2010related genes, such as <jats:italic>Serca1<\/jats:italic> and <jats:italic>Casq1<\/jats:italic>. Double knockout mice show a decrease in calcium decay kinetics after tetanus <jats:italic>in vivo<\/jats:italic>, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes, such as <jats:italic>Tcap<\/jats:italic> and <jats:italic>Fhod3<\/jats:italic>, are linked to sarcomere organization. These results suggest a key role for mTOR signalling in maintaining proper fibre relaxation in skeletal muscle.\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\/tjp15322-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>Skeletal muscle wasting and weakness have been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and are accompanied by altered mammalian target of rapamycin (mTOR) signalling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mammalian target of rapamycin plays a crucial role in the maintenance of muscle mass and functionality.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found that the loss of both mTOR and raptor results in contractile abnormalities, with severe muscle weakness and delayed relaxation following tetanic stimulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results are associated with alterations in the expression of genes involved in sarcomere organization and calcium handling and with an impairment in calcium reuptake after contraction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Taken together, these results provide a mechanistic insight into the role of mTOR in muscle contractility.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283686","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T11:09:30Z","timestamp":1666091370000},"page":"5055-5075","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inducible deletion of raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation"],"prefix":"10.1113","volume":"600","author":[{"given":"Martina","family":"Baraldo","sequence":"first","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Zorzato","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achille Hom\u00e8re Tchampda","family":"Dondjang","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-0684","authenticated-orcid":false,"given":"Alessia","family":"Geremia","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-8707","authenticated-orcid":false,"given":"Leonardo","family":"Nogara","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Georgia","family":"Dumitras","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Canato","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9542-4417","authenticated-orcid":false,"given":"Lorenzo","family":"Marcucci","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"},{"name":"Center for Biosystems Dynamics Research RIKEN  Suita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendrik","family":"Nolte","sequence":"additional","affiliation":[{"name":"Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging\u2010Associated Diseases (CECAD) University of Cologne  Cologne Germany"},{"name":"Center for Molecular Medicine (CMMC) University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4167-5106","authenticated-orcid":false,"given":"Bert","family":"Blaauw","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-7-45"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13569"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2014.11.002"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.200800170"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12496"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101054RR"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2003.07.001"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.10.002"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-29678-2_1723"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn264"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21302"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028090"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00198.2021"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.06.054"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2015.09.013"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.020859"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10226-9"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12854"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43844"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12505"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00833-4"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1212704"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds434"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00388.2004"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1236566"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.051508.135722"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00808-5"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00114-X"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002257R"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2016.06.007"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.08.022"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1215135"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2019.02.003"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0171262"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140935"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00369.x"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.09.020"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq105"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.3233\/JND-160172"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.109.903773"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2014.991572"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000032"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.14.6504"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/35004013"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2012.11.010"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-31154-6"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.138024"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-004-1363-5"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200903131"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12873"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2010"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20107"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13496"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101263"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.07.016"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.059303"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206171200"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)01108-3"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484629"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2021.06.007"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.01.016"},{"key":"e_1_2_5_66_1","first-page":"fj201801653RR","article-title":"The role of raptor in the mechanical load\u2010induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy","author":"You J. S.","year":"2018","journal-title":"Faseb Journal"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12336"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.4.14541"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283686","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP283686","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283686","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T11:08:21Z","timestamp":1692616101000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP283686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":68,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1113\/JP283686"],"URL":"https:\/\/doi.org\/10.1113\/jp283686","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]},"assertion":[{"value":"2022-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}