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

Sci Rep. 2019 May 24;9(1):7799. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / innervation*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Atrophy, Spinal / chemically induced
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / physiopathology*
  • Nerve Regeneration
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology*
  • Schwann Cells / pathology