AD pathology alters basal and contraction-induced gene transcriptional programs in the skeletal muscle of aged females

In addition to neuronal tissue, Alzheimer’s disease (AD) influences the function of peripheral tissues such as skeletal muscle. Recent work suggests the presence of AD pathology limits the responsiveness of young muscles to exercise. However, the extent that AD pathology influences the responsiveness of aged muscle to acute exercise is also unknown. Thus, the purpose of this study was to assess transcriptional changes in aged muscle subjected to acute exercise in the presence of AD pathology. The tibialis anterior (TA) of 20-month-old female 3xTg-AD (model of AD) and B6129F1 wild-type (WT) mice was subjected to a bout of unilateral, electrically evoked, eccentric contractions to mimic resistance exercise. The contralateral TA served as the internal control muscle. Muscles were harvested 4 hours post-contractions. RNA was isolated and subjected to RNA sequencing. Pathway analysis on differentially expressed genes (DEGs) with a >0.5-fold change was performed using DAVID software. Absolute and normalized TA masses (normalized to tibia length) were lower in aged 3xTg-AD mice compared to age-matched WT values. There were 1,309 DEGs (505 upregulated & 804 downregulated) in the non-contracted TA of 3xTg-AD mice compared to the non-contracted TA in WT mice, corresponding to pathways associated with growth regulation, substrate metabolism, inflammation, and structural remodeling. Contractions altered 338 DEGs in WT muscle and 990 DEGs in 3xTg-AD muscle, with only 192 DEGs shared between genotypes. In WT mice, contraction-sensitive DEGs were enriched into pathways related to structural remodeling, extracellular matrix interactions, inflammation, and substrate metabolism. In contrast, contraction-sensitive DEGs in 3xTg-AD mice were mainly enriched into pathways related to inflammation, with others associated with cell survival/growth, and cytoskeletal organization. Those contraction-sensitive DEGs shared by both groups were enriched into pathways related to cytoskeletal organization, growth regulation, inflammation, and cell–cell interactions. Overall, these findings show AD pathology and high force contractions in the presence of AD pathology alter similar gene programs. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.