Alzheimer's Drug Donepezil Boosts Muscle Strength and Mitochondrial Function in Young Mice

Loss of muscle mass and function drives frailty, falls, and reduced resilience in older adults, and exercise is the only widely accepted intervention. Signaling at the neuromuscular junction (NMJ) is central to muscle contraction and mitochondrial adaptation, and it degrades with age. This led the researchers to ask whether a drug that boosts NMJ signaling could help. Their earlier work found that older adults with mild cognitive impairment who took donepezil (DON), an acetylcholinesterase inhibitor, had greater skeletal muscle mitochondrial respiration than untreated counterparts.

To test this directly, the team treated male and female C57Bl/6N mice from about 4-6 weeks of age for 11 weeks. Mice were either wild-type (WT) or Cisd2 knockout (Cisd2KO), a model with some aging-like muscle features (atrophy, mitochondrial defects, impaired proteostasis) that is not true aging. DON was given daily in a flavored treat at roughly 5 mg/kg. Separate cohorts also did treadmill running three days a week, progressing to 35-minute bouts. Outcomes included grip strength, screen hang, beam walk, Y-maze, indirect calorimetry, body composition, muscle fiber size, ex vivo mitochondrial respiration, deuterium-labeled protein synthesis, and RNA sequencing in WT mice.

In WT mice, DON improved screen-hang time at the midpoint and grip strength at the endpoint. It also increased non-resting energy expenditure and improved palmitate-dependent mitochondrial respiration in the gastrocnemius. DON plus exercise produced greater quadriceps mass and fewer beam-walk slips at the end of the study. In Cisd2KO mice, DON increased midpoint screen-hang time and reduced endpoint beam slips. DON interacted with exercise to alter state 3 respiration in Cisd2KO gastrocnemius. Overall, effects in the accelerated-aging model were minimal.

The results suggest that cholinesterase inhibition can partially benefit muscle strength and quality in young, healthy animals, with changes tracking improved mitochondrial respiration. They offer a plausible, though unproven, basis for the earlier human observation. The benefit did not extend broadly to the Cisd2KO model, so it is uncertain whether the effect would hold in genuinely aged or diseased muscle.

Several caveats apply. Mice were young, sample sizes were small (about 10-12 per strain, with few males), and many outcomes were tested, so some findings may be chance. The Cisd2KO model is not natural aging, and the dose and route cannot be directly translated to humans. Only a subset of strength and function measures improved, and the study did not test older animals or people. This summary is based on the abstract and the methods available in the provided text, and the detailed results sections were not available. The work is hypothesis-generating, not evidence for clinical use.