Caloric Restriction Mimetics Slow Aging of Neuromuscular Synapses and Muscle Fibers

Resveratrol and metformin have been shown to mimic some aspects of caloric restriction and exercise. However, it remains unknown if these molecules also slow age-related synaptic degeneration, as previously shown for caloric restriction and exercise. In this study, we examined the structural integrity of neuromuscular junctions (NMJs) in 2-year-old mice treated with resveratrol and metformin starting at 1 year of age. We found that resveratrol significantly slows aging of NMJs in the extensor digitorum longus muscle of 2-year-old mice. Resveratrol also preserved the morphology of muscle fibers in old mice. Although metformin slowed the rate of muscle fiber aging, it did not significantly affect aging of NMJs. Based on these findings, we sought to determine if resveratrol directly affects NMJs. For this, we examined postsynaptic sites, the NMJ region located on the muscle peripheral membrane, on cultured myotubes derived from C2C12 cells. We discovered that resveratrol increases the number of postsynaptic sites on myotubes exhibiting a youthful architecture, suggesting that resveratrol directly affects the NMJ. Altogether, we provide compelling evidence indicating that resveratrol slows aging of NMJs and muscle fibers.