Changes in aging mouse neuromuscular junctions are explained by degeneration and regeneration of muscle fiber...

Vertebrate neuromuscular junctions are highly stable synapses, retaining the morphology they achieve in early postnatal development throughout most of life. However, these synapses undergo dramatic change during aging. The acetylcholine receptors (AChRs) change from smooth gutters into fragmented islands, and the nerve terminals change similarly to be varicosities apposed to these islands. These changes have been attributed to a slow deterioration in mechanisms maintaining the synapse. We have used repeated, vital imaging to investigate how these changes occur in the sternomastoid muscle of aging mice. We have found, contrary to expectation, that individual junctions change infrequently, but change, when it occurs, is sudden and dramatic. The change mimics that reported previously for cases in which muscle fibers are deliberately damaged: most of the AChRs present disappear rapidly and are replaced by a new set of receptors that become fragmented. The fiber segment underneath the synapse has centrally located nuclei, showing that this segment has undergone necrosis, quickly regenerated, and been reinnervated with an altered synapse. We show that necrotic events are common in aged muscle and have likely been missed previously as a cause of the alterations in aging because central nuclei are a transient phenomenon and the necrotic events at the junction infrequent. However, the changes are permanent and accumulate over time. Interventions to reduce the neuromuscular changes during aging should likely focus on making muscle fibers resistant to injury.