Matrix metalloproteinase 3 deletion preserves denervated motor endplates after traumatic nerve injury
Article first published online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 2, pages 210–223, February 2013
How to Cite
Chao, T., Frump, D., Lin, M., Caiozzo, V. J., Mozaffar, T., Steward, O. and Gupta, R. (2013), Matrix metalloproteinase 3 deletion preserves denervated motor endplates after traumatic nerve injury. Ann Neurol., 73: 210–223. doi: 10.1002/ana.23781
- Issue published online: 22 MAR 2013
- Article first published online: 31 DEC 2012
- Accepted manuscript online: 1 OCT 2012 06:05AM EST
- Manuscript Accepted: 24 SEP 2012
- Manuscript Revised: 29 AUG 2012
- Manuscript Received: 12 JUN 2012
Traumatic peripheral nerve injuries often produce permanent functional deficits despite optimal surgical and medical management. One reason for the impaired target organ reinnervation is degradation of motor endplates during prolonged denervation. Here we investigate the effect of preserving agrin on the stability of denervated endplates. Because matrix metalloproteinase 3 (MMP3) is known to degrade agrin, we examined the changes in endplate structure following traumatic nerve injury in MMP3 knockout mice.
After creation of a critical size nerve defect to preclude reinnervation, we characterized receptor area, receptor density, and endplate morphology in denervated plantaris muscles in wild-type and MMP3 null mice. The level of agrin and muscle-specific kinase (MuSK) was assessed at denervated endplates. In addition, denervated muscles were subjected to ex vivo stimulation with acetylcholine. Finally, reinnervation potential was compared after long-term denervation.
In wild-type mice, the endplates demonstrated time-dependent decreases in area and receptor density and conversion to an immature receptor phenotype. In striking contrast, all denervation-induced changes were attenuated in MMP3 null mice, with endplates retaining their differentiated form. Agrin and MuSK were preserved in endplates from denervated MMP3 null animals. Furthermore, denervated muscles from MMP3 null mice demonstrated greater endplate efficacy and reinnervation.
These results demonstrate a critical role for MMP3 in motor endplate remodeling, and reveal a potential target for therapeutic intervention to prevent motor endplate degradation following nerve injury. ANN NEUROL 2013;73:210–223