Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

Abstract

Myotonic dystrophy types 1 (DM1) and 2 (DM2) are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM), a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6) myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling.

• Authors: Masayuki Nakamori, Kohei Hamanaka, James D Thomas, Eric T Wang, Yukiko K Hayashi, Masanori P Takahashi, Maurice S Swanson, Ichizo Nishino, Hideki Mochizuki
• Journal: Cell reports (Cell Rep) Vol. 21 Issue 5 Pg. 1240-1252 (Oct 31 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 29091763 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ATXN7 protein, human
• Ataxin-7
• CCCTC-Binding Factor
• CTCF protein, human
• DMPK protein, human
• FXR1 protein, human
• Interleukin-6
• Muscle Proteins
• NRAP protein, human
• RNA-Binding Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Myotonin-Protein Kinase

Topics

• Alternative Splicing
• Ataxin-7 (genetics, metabolism)
• Binding Sites
• CCCTC-Binding Factor (genetics, metabolism)
• CpG Islands
• DNA Methylation
• Humans
• Infant
• Interleukin-6 (metabolism)
• Muscle Proteins (genetics, metabolism)
• Muscles (metabolism)
• Myotonic Dystrophy (genetics, metabolism, pathology)
• Myotonin-Protein Kinase (genetics)
• Protein Binding
• RNA-Binding Proteins (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (physiology)
• Transcription, Genetic
• Trinucleotide Repeat Expansion
• Up-Regulation