Donepezil treatment, alone or combined with exercise, enhances skeletal muscle function in healthy and advanced aging disease mouse models.

Reduced muscle mass and function are hallmarks of aging, increased frailty, and reduced resilience. There are no clinically approved interventions besides exercise to improve muscle quality and function in the elderly. We recently found that older participants with mild cognitive impairment (MCI) who took the acetylcholinesterase inhibitor donepezil (DON) had greater skeletal muscle mitochondrial respiratory capacity than nontreated counterparts. Here we tested whether DON treatment or DON + exercise on treadmill (EX) improved muscle and mitochondrial function in male and female mice that were young adult wild type (WT) or with an early aging phenotype [CDGH iron-sulfur domain 2 (Cisd2) knockout mice] (Cisd2KO; n = 10-12 total mice/strain) from 4 to 15 wk of age. In WT mice, DON improved screen hanging time at the midpoint and increased grip strength at the endpoint of the 11-wk study. Furthermore, DON increased nonresting energy expenditure and improved palmitate-dependent mitochondrial respiration in the gastrocnemius muscle in WT, while interacting with exercise to alter state 3 respiration in Cisd2KO gastrocnemius. DON + EX resulted in greater WT quadriceps mass and reduced endpoint beam walk slipping, whereas DON increased midpoint screen hang time and reduced endpoint beam slips in the Cisd2KO. Overall, this study provides preliminary evidence that cholinesterase inhibition partially benefits skeletal muscle strength and quality in young healthy mice, changes that are associated with improvements in mitochondrial respiration. However, cholinesterase inhibition had minimal effects in a model of advanced aging. Further research is needed to determine whether cholinesterase inhibitors can combat age-related muscle decline.NEW & NOTEWORTHY Aging is often accompanied by a decline in muscle mass and function, with limited effective treatments. The study provides novel insights into the potential of donepezil, an acetylcholinesterase medication primarily used for dementia, to improve skeletal muscle health and function.