Muscle fiber-type specific terminal Schwann cell pathology leads to sprouting deficits following partial denervation in SOD1G93A mice

Julia M. Harrison, Victor F. Rafuse

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the progressive death of motoneurons and denervation of muscle fibers. To restore motor function, surviving motoneurons in partially denervated muscles typically sprout axons to reinnervate denervated endplates. However, studies on the SOD1G93A rodent models of ALS indicate that sprouting is significantly limited in fast, but not slow, twitch muscles after disease onset. This limitation hastens the rate of muscle weakness and loss of motor function. The causes of this limitation are currently unknown. Sprouting could be limited because the SOD1G93A mutation weakens motoneurons making them incapable of expanding their field of innervation. Alternatively, motoneurons may be capable of sprouting, but unable to do so due to the loss of a permissive sprouting environment. To distinguish between the two possibilities, we compared the sprouting capacity of motoneuron subtypes by partially denervating the fast twitch plantaris (composed of type IIa/IIb muscle fibers) and slow twitch soleus muscles (type I/IIa fibers) prior to disease onset and weakening in SOD1G93A and WT mice. We found that only motoneurons innervating the SOD1G93A plantaris had a limited sprouting capacity. This was correlated with the selective loss of terminal Schwann cells (TSCs) at IIb fibers and an increase in macrophage infiltration. Treating SOD1G93A mice with the tyrosine kinase inhibitor, masitinib, significantly reduced infiltration, prevented TSC loss, and increased the sprouting capacity to near normal. These results suggest that TSCs at denervated type IIb muscle fibers are aberrantly targeted by infiltrating macrophages in SOD1G93A mice, and their loss accounts, at least in part, for the compromised sprouting capacity of the largest motoneurons during early stages of ALS.

Original languageEnglish
Article number105052
JournalNeurobiology of Disease
Volume145
DOIs
Publication statusPublished - Nov 2020

Bibliographical note

Funding Information:
This study was supported by Grant PJT 147893 from the Canadian Institutes of Health Research (V.F.R). J.M.H. was funded in part by a graduate student award from the Natural Sciences and Engineering Research Council of Canada. The SC-71 and BF-F3 antibodies were obtained from the Developmental Studies Hybridoma Bank under the auspices of the National Institute of Child Health and Human Development and maintained by the University of Iowa Department of Biology. Finally, the authors would also like to acknowledge Simone LaForest for animal husbandry and genotyping.

Funding Information:
This study was supported by Grant PJT 147893 from the Canadian Institutes of Health Research (V.F.R). J.M.H. was funded in part by a graduate student award from the Natural Sciences and Engineering Research Council of Canada . The SC-71 and BF-F3 antibodies were obtained from the Developmental Studies Hybridoma Bank under the auspices of the National Institute of Child Health and Human Development and maintained by the University of Iowa Department of Biology. Finally, the authors would also like to acknowledge Simone LaForest for animal husbandry and genotyping.

Publisher Copyright:
© 2020

ASJC Scopus Subject Areas

  • Neurology

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