Skeletal muscle fatigue resistance is differentially affected in 8-month-old male and female hAβ-KI mice.

Approximately 95% of Alzheimer's disease (AD) diagnoses are sporadic onset, present after the age of 65, and arising from a combination of non-modifiable and modifiable factors. This underscores the potential to identify early systemic changes that may contribute to disease development. One factor may be skeletal muscle atrophy, which has been associated with cognitive decline, although the exact relationship between skeletal muscle and the brain is unknown. Furthermore, whether muscle atrophy begins prior to or after the onset of AD remains elusive. The humanized amyloid-beta knock-in mouse (hAβ-KI) exhibits age-related cognitive decline, insoluble Aβ accumulation, inflammation and microglial activation, making it a useful model of sporadic AD. However, characterization of skeletal muscle changes with aging has yet to be examined. Here, we assess skeletal muscle form and function of the hAβ-KI mouse at 8 and 15 months of age, before and after onset of cognitive decline, through assessment of whole-body lean mass percentage, isolated muscle contraction of the extensor digitorum longus (EDL) and soleus muscle, and fiber type analysis of male and female mice. Whole-body lean mass declined over time in all mice; however, only male hAβ-KI mice had a significant change in body mass and lean mass over the study. At 8-months-old, the isolated EDL of male hAβ-KI mice fatigued faster than the WT mice, but there were no differences at 15 months-old nor fiber type composition at either age. Alternatively, the isolated EDL and soleus of 8-month-old hAβ-KI female mice fatigued slower compared to the WT mice, and there were no differences at 15 months nor fiber type composition at either age. This preliminary characterization work suggests sex-dependent differences in isolated muscle fatigue prior to cognitive decline in the hAβ-KI mouse model of sporadic AD.