Factors affecting denervation-like changes at the neuromuscular junction during aging.

The ability to sustain synaptic transmission diminishes with aging. To determine whether this is accompanied by alterations in the structure of the synapse, end-plate architecture was examined in EDL muscles from 10- to 25-month rats. There was a significant age-related increase in end-plate area and a decrease in the number of nerve terminals per end plate. Furthermore, the percentage of end plates with ultraterminal sprouts increased dramatically with age. To compare the morphological changes associated with aging to the changes in response to denervation, EDL muscles from 10- and 25-month animals were partially denervated. Both end-plate area and ultraterminal sprouting increased, while terminal number decreased following denervation in the 10-month muscles. To determine whether the age- and denervation-associated changes were accompanied by alterations in muscle-derived nerve-outgrowth factors, in vitro assays were performed. Neurite outgrowth was quantified from embryonic motoneurons incubated with muscle extract, or grown on cryostat-cut muscle cross sections from 10- and 25-month innervated and denervated EDL muscles. Both aged and denervated muscles induced greater degrees of neurite outgrowth compared with younger innervated muscles. Innervation to the EDL was then examined, and signs of axonal degeneration were observed. It is suggested that aging is associated with alterations in the motor axon to the EDL muscle. These changes are manifest at the neuromuscular junction. In turn, the muscle responds as if it were in a state of functional denervation.