{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:56:30Z","timestamp":1792598190196,"version":"4.5.0"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T00:00:00Z","timestamp":1634428800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Alzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age\u2010associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy\u2010induced acceleration of AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pre\u2010symptomatic young 5XFAD or non\u2010transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14\u00a0days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two\u2010dimensional polyacrylamide gel electrophoresis (2D\u2010PAGE). Protein expressions in the CM were analysed by matrix\u2010assisted laser desorption\/ionization\u2010time\u2010of\u2010flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real\u2010time reverse transcription polymerase chain reaction and histological analysis confirmed the expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Casting for 2\u00a0weeks reduced skeletal muscle weight. Object recognition memory in the cast\u2010attached 5XFAD mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a07, training vs. test, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.3390) was impaired than that in age\u2010matched wildtype (<jats:italic>n<\/jats:italic>\u00a0=\u00a07, training vs. test, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0523) and non\u2010cast 5XFAD mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a07, training vs. test, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0473). On 2D\u2010PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast\u2010attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (<jats:italic>n<\/jats:italic>\u00a0=\u00a03, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0064), plasma (<jats:italic>n<\/jats:italic>\u00a0=\u00a03, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0386), and hippocampus (<jats:italic>n<\/jats:italic>\u00a0=\u00a03, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0164) were increased in cast\u2010attached 5XFAD mice than those in non\u2010cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2\u00a0weeks induced memory deficits in young 5XFAD mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a04, training vs. test, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.6764). Lipocalin\u20102 (<jats:italic>Lcn2<\/jats:italic>) messenger RNA (mRNA), neuroinflammation\u2010associated factor, was increased in the hippocampus in hemopexin\u2010infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. <jats:italic>Lcn2<\/jats:italic> mRNA levels in the hippocampus were also increased by cast\u2010immobilization of the hindlimbs (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0043).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12830","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T02:54:03Z","timestamp":1634698443000},"page":"2199-2210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Skeletal muscle atrophy\u2010induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Tsukasa","family":"Nagase","sequence":"first","affiliation":[{"name":"Section of Neuromedical Science, Division of Bioscience, Institute of Natural Medicine University of Toyama  Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5738-4258","authenticated-orcid":false,"given":"Chihiro","family":"Tohda","sequence":"additional","affiliation":[{"name":"Section of Neuromedical Science, Division of Bioscience, Institute of Natural Medicine University of Toyama  Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.11.192"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-019-0609-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-021-01125-y"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.11.1509"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.06.001"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.4669"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.0629"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70072-2"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.12221"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2019.12.014"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.12825"},{"key":"e_1_2_10_13_1","first-page":"733","article-title":"The prevalence of dementia and cognitive impairment in hospitals","volume":"115","author":"Bickel H","year":"2018","journal-title":"Dtsch Arztebl 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