How Age Impairs the Response of the Neuromuscular Junction to Nerve Transection and Repair: An Experimental Study in Rats

Age is the most important predictor of clinical outcome after peripheral nerve injury. The stability of the neuromuscular junction (NMJ) after denervation is thought to be central to neuromuscular recovery. Stability is characterized by maintenance of the motor endplate and mRNA upregulation of the constituent nicotinic acetylcholinergic receptor (nAChR) subtypes and the muscle regulatory factors (MRFs). The purpose of this study was to determine the effect of age on the recovery and stability of the postsynaptic NMJ after peripheral nerve injury. Young and aged rats underwent transection and repair of the tibial nerve. At 1, 2, 4, 8, or 16 weeks following transection, the gastrocnemius was examined for electrical recovery, NMJ fragmentation and endplate area, mRNA, and protein levels of the MRFs and nAChR subtypes. After nerve injury, aged NMJ exhibited significant fragmentation and loss of motor endplate area while the young NMJ remained relatively stable. Concomitantly, age impaired peak upregulation of the MRFs and nAChRs. However, expression of gamma-nAChR and myogenin after nerve injury was not affected by age. These data support the claim that upregulation of the nAChRs and MRFs may play an important role in maintaining NMJ stability following nerve transection and repair. Furthermore, expression of gamma-nAChR and myogenin does not appear to prevent age-related NMJ fragmentation and loss of endplate area after nerve injury. These impairments of the aged NMJ response to injury may contribute to the poor neuromuscular recovery seen after nerve injury in this population. (C) 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:385-393, 2009