Nerve sprouting capacity in a pharmacologically induced mouse model of spinal muscular atrophy

Mendell Rimer,Bonnie L Seaberg,Robert Louis Hastings,Steven Lam,Chien-Ping Ko,Sergey Paushkin,Young Il Lee,Friedrich Metzger,Wesley J Thompson,Pei-Fen Yen,Zhihua Feng

doi:10.1038/s41598-019-44222-2

Abstract

Spinal muscular atrophy (SMA) is caused by loss-of-function mutations in the survival of motoneuron gene 1 (SMN1). SMA is characterized by motoneuron death, skeletal muscle denervation and atrophy. Disease severity inversely correlates with copy number of a second gene (SMN2), which harbors a splicing defect that causes the production of inadequate levels of functional SMN protein. Small molecules that modify SMN2 splicing towards increased production of functional SMN significantly ameliorate SMA phenotypes in mouse models of severe SMA. At suboptimal doses, splicing modifiers, such as SMN-C1, have served to generate mice that model milder SMA, referred to as pharmacological SMA mice, which survive into early adulthood. Nerve sprouting at endplates, known as terminal sprouting, is key to normal muscle fiber reinnervation following nerve injury and its promotion might mitigate neuromuscular symptoms in mild SMA. Sprouting has been difficult to study in severe SMA mice due to their short lifespan. Here, we show that pharmacological SMA mice are capable of terminal sprouting following reinnervation that is largely SMN-C1 dose-independent, but that they display a reinnervation delay that is critically SMN-C1 dose-dependent. Data also suggest that SMN-C1 can induce by itself a limited terminal sprouting response in SMA and wild-type normally-innervated endplates.

Highlights

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motoneuron loss, muscle denervation and atrophy, caused by a scarcity of full length survival of motoneuron (SMN) protein[1]
Age- and strain-matched, wild type (WT) mice injected with dimethyl sulfoxide (DMSO) vehicle were used as controls
Our data show that: (i) Short nerve terminal sprouts at non-denervated endplates were more abundant in soleus muscle (SOL) from SMN-C1 treated SMA mice than in DMSO WT controls

Summary

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motoneuron loss, muscle denervation and atrophy, caused by a scarcity of full length survival of motoneuron (SMN) protein[1]. A pharmacologically-induced SMA mouse model was developed[9] by treating SMNΔ7 mice with a suboptimal dose of a SMN2 splicing modifier (SMN-C1)[10], which increases the levels of full-length SMN produced from SMN2 by promoting exon 7 inclusion into mature transcripts. These mice have milder SMA phenotypes than SMNΔ7 mice and survive into adulthood, allowing testing of SMA treatments after disease onset. Terminal sprouts from an endplate can innervate nearby endplates that are not contacted by the main axonal branches This compensatory nerve sprouting is important to normal muscle reinnervation following nerve injury in adults[17], and its promotion might mitigate neuromuscular symptoms in mild SMA. We tested whether nerve sprouting occurs after reinnervation in the pharmacological SMA model mice and how it is impacted by the dose of SMN-C1 treatment

Methods

Results

Conclusion