Human skeletal muscle mitochondrial pathways are impacted by a neuropathologic diagnosis of Alzheimer's disease
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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001329 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 1095-953X |