{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T22:44:29Z","timestamp":1778107469877,"version":"3.51.4"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T00:00:00Z","timestamp":1641686400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006380","name":"Rehabilitation Research and Development Service","doi-asserted-by":"publisher","award":["B7756R"],"award-info":[{"award-number":["B7756R"]}],"id":[{"id":"10.13039\/100006380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006380","name":"Rehabilitation Research and Development Service","doi-asserted-by":"publisher","award":["CDA\u20102 IK2RX002781\u201001"],"award-info":[{"award-number":["CDA\u20102 IK2RX002781\u201001"]}],"id":[{"id":"10.13039\/100006380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006380","name":"Rehabilitation Research and Development Service","doi-asserted-by":"publisher","award":["B2020C"],"award-info":[{"award-number":["B2020C"]}],"id":[{"id":"10.13039\/100006380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006380","name":"Rehabilitation Research and Development Service","doi-asserted-by":"publisher","award":["B9212C"],"award-info":[{"award-number":["B9212C"]}],"id":[{"id":"10.13039\/100006380","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":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The role of Numb, a protein that is important for cell fate and development and that, in human muscle, is expressed at reduced levels with advanced age, was investigated; adult mice skeletal muscle and its localization and function within myofibres were determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Numb expression was evaluated by western blot. Numb localization was determined by confocal microscopy. The effects of conditional knock out (cKO) of Numb and the closely related gene Numb\u2010like in skeletal muscle fibres were evaluated by\n                      <jats:italic>in situ<\/jats:italic>\n                      physiology, transmission and focused ion beam scanning electron microscopy, three\u2010dimensional reconstruction of mitochondria, lipidomics, and bulk RNA sequencing. Additional studies using primary mouse myotubes investigated the effects of Numb knockdown on cell fusion, mitochondrial function, and calcium transients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Numb protein expression was reduced by ~70% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01) at 24 as compared with 3\u00a0months of age in gastrocnemius and tibialis anterior muscle. Numb was localized within muscle fibres as bands traversing fibres at regularly spaced intervals in close proximity to dihydropyridine receptors. The cKO of Numb and Numb\u2010like reduced specific tetanic force by 36% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), altered mitochondrial spatial relationships to sarcomeric structures, increased Z\u2010line spacing by 30% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001), perturbed sarcoplasmic reticulum organization and reduced mitochondrial volume by over 80% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01). Only six genes were differentially expressed in cKO mice:\n                      <jats:italic>Itga4<\/jats:italic>\n                      ,\n                      <jats:italic>Sema7a<\/jats:italic>\n                      ,\n                      <jats:italic>Irgm2<\/jats:italic>\n                      ,\n                      <jats:italic>Vezf1<\/jats:italic>\n                      ,\n                      <jats:italic>Mib1<\/jats:italic>\n                      , and\n                      <jats:italic>Tmem132a<\/jats:italic>\n                      . Several lipid mediators derived from polyunsaturated fatty acids through lipoxygenases were up\u2010regulated in Numb cKO skeletal muscle: 12\u2010HEPE was increased by ~250% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and 17,18\u2010EpETE by ~240% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). In mouse primary myotubes, Numb knockdown reduced cell fusion (~20%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01) and delayed the caffeine\u2010induced rise in cytosolic calcium concentrations by more than 100% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings implicate Numb as a critical factor in skeletal muscle structure and function and suggest that Numb is critical for calcium release. We therefore speculate that Numb plays critical roles in excitation\u2013contraction coupling, one of the putative targets of aged skeletal muscles. These findings provide new insights into the molecular underpinnings of the loss of muscle function observed with sarcopenia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12907","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T23:11:42Z","timestamp":1641769902000},"page":"454-466","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Numb is required for optimal contraction of skeletal muscle"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5281-4263","authenticated-orcid":false,"given":"Rita","family":"De Gasperi","sequence":"first","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA  Bronx NY USA"},{"name":"Department of Psychiatry and Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenglin","family":"Mo","sequence":"additional","affiliation":[{"name":"Bone\u2010Muscle Research Center, College of Nursing &amp; Health Innovation The University of Texas at Arlington  Arlington TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniella","family":"Azulai","sequence":"additional","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA  Bronx NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Bone\u2010Muscle Research Center, College of Nursing &amp; Health Innovation The University of Texas at Arlington  Arlington TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren M.","family":"Harlow","sequence":"additional","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA  Bronx NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yating","family":"Du","sequence":"additional","affiliation":[{"name":"Bone\u2010Muscle Research Center, College of Nursing &amp; Health Innovation The University of Texas at Arlington  Arlington TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Graham","sequence":"additional","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA  Bronx NY USA"},{"name":"Department of Medicine Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangping","family":"Pan","sequence":"additional","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. 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Peters VA  Bronx NY USA"},{"name":"Department of Medicine Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York NY USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York NY USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fred","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Medicine Icahn School of Medicine at Mount Sinai  New York NY USA"},{"name":"Department of Geriatrics and Palliative Medicine Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashleigh M.","family":"Raczkowski","sequence":"additional","affiliation":[{"name":"New York Structural Biology Center  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William A.","family":"Bauman","sequence":"additional","affiliation":[{"name":"National Center for the Medical Consequences of Spinal Cord Injury, James J. 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