Chelsea N. Johnson , Mara R. Evans , Anneka E. Blankenship , Casey S. John , Michaella J. Rekowski , Michael P. Washburn , Andy Phan , Cynthia M. Gouvion , Mohammad Haeri , Russell H. Swerdlow , Paige C. Geiger , Jill K. Morris
{"title":"Human skeletal muscle mitochondrial pathways are impacted by a neuropathologic diagnosis of Alzheimer's disease","authors":"Chelsea N. Johnson , Mara R. Evans , Anneka E. Blankenship , Casey S. John , Michaella J. Rekowski , Michael P. Washburn , Andy Phan , Cynthia M. Gouvion , Mohammad Haeri , Russell H. Swerdlow , Paige C. Geiger , Jill K. Morris","doi":"10.1016/j.nbd.2025.106916","DOIUrl":null,"url":null,"abstract":"<div><div>Alzheimer's disease (AD) is associated with reduced lean mass and impaired skeletal muscle mitochondrial and motor function. Although primary mitochondrial defects in AD may underlie these findings, molecular alterations in AD have not been thoroughly examined in human skeletal muscle. Here, we used two human skeletal muscle types, quadriceps (<em>n</em> = 81) and temporalis (<em>n</em> = 66), to compare the proteome of individuals with a neuropathologic AD diagnosis based on AD Neuropathologic Change (ADNPC+: <em>n</em> = 54 temporalis, 44 quadriceps) to controls (ADNPC-: <em>n</em> = 27 temporalis, 22 quadriceps). We determined the effects of ADNPC status within each muscle and within apolipoprotein E4 (<em>APOE4</em>) carriers and <em>APOE4</em> non-carriers. Pathways that support mitochondrial metabolism, including oxidative phosphorylation, were downregulated in skeletal muscle of ADNPC+ versus ADNPC- individuals. Similar mitochondrial effects were observed across muscle types and <em>APOE4</em> carrier groups, but nearly four times as many proteins were altered in temporalis versus quadriceps tissue and mitochondrial effects were most pronounced in <em>APOE4</em> carriers compared to <em>APOE4</em> non-carriers. Of all detected oxidative phosphorylation proteins, the expression of ∼29–61 % (dependent on muscle/<em>APOE4</em> carrier group) significantly correlated with AD progression, ranked by Clinical Dementia Rating and ADNPC scores. Of these, 23 proteins decreased in expression with greater AD progression in all skeletal muscle type and <em>APOE4</em> carrier groups. This is the first study to assess differences in the human skeletal muscle proteome in the context of AD. Our work shows that systemic mitochondrial alterations in AD extend to skeletal muscle and these effects are amplified by <em>APOE4</em> and correlate with AD progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106916"},"PeriodicalIF":5.1000,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969996125001329","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Alzheimer's disease (AD) is associated with reduced lean mass and impaired skeletal muscle mitochondrial and motor function. Although primary mitochondrial defects in AD may underlie these findings, molecular alterations in AD have not been thoroughly examined in human skeletal muscle. Here, we used two human skeletal muscle types, quadriceps (n = 81) and temporalis (n = 66), to compare the proteome of individuals with a neuropathologic AD diagnosis based on AD Neuropathologic Change (ADNPC+: n = 54 temporalis, 44 quadriceps) to controls (ADNPC-: n = 27 temporalis, 22 quadriceps). We determined the effects of ADNPC status within each muscle and within apolipoprotein E4 (APOE4) carriers and APOE4 non-carriers. Pathways that support mitochondrial metabolism, including oxidative phosphorylation, were downregulated in skeletal muscle of ADNPC+ versus ADNPC- individuals. Similar mitochondrial effects were observed across muscle types and APOE4 carrier groups, but nearly four times as many proteins were altered in temporalis versus quadriceps tissue and mitochondrial effects were most pronounced in APOE4 carriers compared to APOE4 non-carriers. Of all detected oxidative phosphorylation proteins, the expression of ∼29–61 % (dependent on muscle/APOE4 carrier group) significantly correlated with AD progression, ranked by Clinical Dementia Rating and ADNPC scores. Of these, 23 proteins decreased in expression with greater AD progression in all skeletal muscle type and APOE4 carrier groups. This is the first study to assess differences in the human skeletal muscle proteome in the context of AD. Our work shows that systemic mitochondrial alterations in AD extend to skeletal muscle and these effects are amplified by APOE4 and correlate with AD progression.
期刊介绍:
Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.