A Cross-Sectional Study of Aging at the Mouse Neuromuscular Junction and Effects of an Experimental Therapeutic Approach for Dynapenia

Despite prior efforts to understand and target dynapenia (age-induced loss of muscle strength), this condition remains a major challenge that reduces the quality of life in the aged population. We have focused on the neuromuscular junction (NMJ) where changes in structure and function have rarely been systematically studied as a dynamic and progressive process. Our cross-sectional study found neurotransmission at the male mouse NMJ to be biphasic, displaying an early increase followed by a later decrease, and this phenotype was associated with structural changes to the NMJ. A cross-sectional characterization showed that age-induced alterations fell into four age groups: Young Adult (3-6 months), Adult (7-18 months), Early Aged (19-24 months), and Later Aged (25-30 months). We then utilized a small molecule therapeutic candidate, GV-58, applied acutely during the Later Aged stage to combat age-induced reductions in transmitter release by increasing calcium influx during an action potential, which resulted in a significant increase in transmitter release. This comprehensive study of neuromuscular aging at the NMJ will enable future research to target critical time points for therapeutic intervention