Peripheral nerve injury, regeneration, and recovery: A tribute to David Kline

David Kline’s clinical and surgical skills are legendary. This review compares crush and transection injuries, first, by reviewing the molecular and structural changes in injured neurons, denervated distal nerve stumps and muscles, and second, nerve regeneration. Regenerating axons ‘wonder’ in the injury site before they “’stagger” across the site and into the endoneurial tubes of the denervated distal nerve stump with long delays. Brief, 20Hz electrical stimulation (ES) hastens axon outgrowth to significantly accelerate nerve regeneration and muscle reinnervation in animals and human subjects, even after delayed surgical repair. A conditioning lesion of a nerve injury prior to a transection injury, by accelerating both axon outgrowth and axonal regeneration rate, is superior to ES but is applicable for nerve graft and nerve transfer reconstruction surgeries. After crush injuries, regenerating axons re-enter their original endoneurial tubes to reinnervate their original muscle fibers, reestablishing the normal mosaic distribution. After transection injuries, regenerating axons fail to find original endoneurial tubes. Thereby reinnervated muscle fibers ‘clump’ with progressively more clumping as numbers of regenerating nerves decline. The normal positive correlations of nerve and muscle unit (the muscle fibers supplied by one motoneuron) size and contractile force, as the basis for motor unit orderly recruitment (the size principle), return when the heterogeneous reinnervated muscle fibers are respecified as one muscle fiber type. We verified the prediction of the size principle that the amount of daily neuromuscular activity determines nerve and muscle properties by imposing either 50%, 5% and 0.5% daily activities on the neuromuscular system.