Peripheral nerves preferentially regenerate in intramuscular endoneurial tubes to reinnervate denervated skeletal muscles.

Schwann cells are essential for peripheral nerve regeneration but, over short distances in acellular nerve grafts, extracellular matrix (ECM) molecules can support growth. The ECM molecules are present also on denervated muscle surfaces where they can support nerve growth. In this study, we addressed the efficacy of the ECM molecules of denervated muscle to support nerve fiber regeneration and muscle reinnervation. In the hindlimb of Sprague-Dawley rats, the proximal stump of the transected posterior tibial nerve, was cross-sutured to the distal nerve stump (NN) of each of three denervated muscles, tibialis anterior, extensor digitorum longus, and soleus, or implanted onto the denervated muscles' surfaces (N-M), proximal or distal to the endplate zone. Recordings of muscle and motor unit (MU) isometric forces and silver/cholinesterase histochemical staining of longitudinal muscle cryosections were used to determine the numbers of reinnervated MUs and the spatial course of regenerating nerve fibers, respectively. MU numbers declined significantly after N-M (>50%) as compared to those after NN. Muscle forces were reduced despite each nerve reinnervating up to three times the normal MU muscle fiber number. Regenerating nerves 'streamed' from the N-M site either proximal or distal to endplate zones toward the denervated intramuscular endoneurial tubes, with reduced numbers reinnervating endplates. We conclude that there is preferential reinnervation through the endoneurial tube and that it is important to drive implanted nerve fibers to enter endoneurial tubes for optimal muscle reinnervation. Schwann cells play the essential role in guiding regenerating nerve fibers to reinnervate denervated muscle fibers.