Agrin Influences Botulinum Neurotoxin A-Induced Nerve Sprouting via miR-144-agrin-MuSK Signaling

Lin Ma; Lizhen Pan; Wuchao Liu; Ying Liu; Xuerui Xiang; Yougui Pan; Xiaolong Zhang; Lingjing Jin

doi:10.3389/fcell.2020.00015

Agrin Influences Botulinum Neurotoxin A-Induced Nerve Sprouting via miR-144-agrin-MuSK Signaling

Front Cell Dev Biol. 2020 Jan 30:8:15. doi: 10.3389/fcell.2020.00015. eCollection 2020.

Authors

Lin Ma^{1

2}, Lizhen Pan^{2

3}, Wuchao Liu^{2

3}, Ying Liu³, Xuerui Xiang³, Yougui Pan³, Xiaolong Zhang³, Lingjing Jin^{2

3}

Affiliations

¹ Department of Interventional Radiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
² Neurotoxin Research Center, Tongji University School of Medicine, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education of the People's Republic of China, Shanghai, China.
³ Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

Botulinum neurotoxin (BoNT) has become a powerful therapeutic tool, and is extensively used in aesthetic medicine and in the treatment of neurological disorders. However, its duration of effect is limited, mainly owing to nerve sprouting. Inhibition of nerve sprouting to prolong the effective duration of BoNT is therefore of great clinical interest. However, appropriate interventional strategies to accomplish this are currently unavailable. In this study, we determined the role of the neurogenic regulator agrin in BoNT type A (BoNT/A)-induced nerve sprouting in a rat model. We then determined whether agrin could be used as an interventional target for prolonging the duration of effect of BoNT/A, and made a preliminary study of the upstream and downstream regulatory mechanisms by which agrin could influence the effective duration of BoNT/A. Our results showed that agrin was involved in the regulation of BoNT/A-induced nerve sprouting, and blocking of agrin function with anti-agrin antibody temporarily could delay muscle strength recovery and prolong the duration of BoNT/A effect. Moreover, agrin influenced the duration of BoNT/A effect by regulating downstream myogenic muscle-specific receptor tyrosine kinase (MuSK), and was simultaneously regulated by upstream miR-144. In conclusion, agrin could regulate BoNT/A-induced nerve sprouting through miR-144-agrin-MuSK signaling; it influences the effective duration of BoNT/A, and could find clinical application as an interventional target for prolonging the effect of BoNT/A.

Keywords: agrin; botulinum neurotoxin; microRNA; muscle-specific receptor tyrosine kinase; nerve sprouting.