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Cell Rep. 2017 Oct 31;21(5):1240-1252. doi: 10.1016/j.celrep.2017.10.018.

Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

Author information

1
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Electronic address: mnakamor@neurol.med.osaka-u.ac.jp.
2
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
3
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
4
Department of Pathophysiology, Tokyo Medical University, Shinjuku, Tokyo 160-0022, Japan.
5
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
6
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

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.

KEYWORDS:

CTCF; ER stress; IL-6; NF-κB; cytokine; muscular dystrophy; splicing; trinucleotide

PMID:
29091763
PMCID:
PMC5689469
DOI:
10.1016/j.celrep.2017.10.018
[Indexed for MEDLINE]
Free PMC Article

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