Ernst_2025_J.Appl.Physiol.(1985)__

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 non-treated counterparts. Here we tested if 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 weeks of age. In WT mice, DON improved screen hanging time at the midpoint and increased grip strength at the endpoint of the 11-week study. Further, DON increased non-resting energy expenditure and improved palmitate-dependent mitochondrial respiration in 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 while 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 if cholinesterase inhibitors can combat age-related muscle decline.