Characterization of sex-dependent skeletal muscle alterations in the 3xTg Alzheimer’s disease mouse model

Alzheimer's disease (AD) is increasingly recognized as a systemic condition with effects beyond the central nervous system. Skeletal muscle dysfunction, including sarcopenia and reduced physical performance, is prevalent in AD patients, yet the underlying mechanisms remain poorly understood. In this study, we characterized skeletal muscle alterations in male and female 3xTg-AD mice at 3, 6, and 12 months of age and compared them to age- and sex-matched B6129 controls. We measured body composition, muscle function, and skeletal muscle parameters including fiber type distribution, cross-sectional area (CSA), and neural cell adhesion molecule (NCAM) expression. Our findings revealed early-onset and progressive impairments of skeletal muscle mass, morphology, and function in 3xTg-AD mice, with sex-specific differences. Male mice exhibited reduced lean mass, muscle weight, and torque generation as early as 3 months and decreased CSA of type IIB and IIX fibers and increased NCAM expression by 12 months, indicating a potential neuromuscular junction deficiency. Female mice in this study generally exhibited a milder phenotype. Together, these results identify skeletal muscle dysfunction as an early and sex-dependent feature of AD pathology in 3xTg-AD mice. Our study underscores the importance of considering systemic effects in AD and highlights skeletal muscle as a potential target for therapeutic intervention aimed at preserving mobility and quality of life in affected individuals.