Aberrant Myokine Signaling in Congenital Myotonic Dystrophy
Summary: 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 on...
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doaj-1673442e67eb40de8ee555f59692717c2020-11-25T01:32:29ZengElsevierCell Reports2211-12472017-10-0121512401252Aberrant Myokine Signaling in Congenital Myotonic DystrophyMasayuki Nakamori0Kohei Hamanaka1James D. Thomas2Eric T. Wang3Yukiko K. Hayashi4Masanori P. Takahashi5Maurice S. Swanson6Ichizo Nishino7Hideki Mochizuki8Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Corresponding authorDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, JapanDepartment of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USADepartment of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USADepartment of Pathophysiology, Tokyo Medical University, Shinjuku, Tokyo 160-0022, JapanDepartment 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, JapanDepartment of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USADepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, JapanDepartment of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanSummary: 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. : Congenital myotonic dystrophy (CDM) manifests characteristic genetic (very large CTG repeat expansions), epigenetic (CpG hypermethylation upstream of the repeat), and phenotypic (muscle immaturity) features not seen in adult DM. Nakamori et al. find phenotype-genotype and epigenotype correlation in CDM muscle and reveal involvement of the IL-6 myokine signaling pathway in the disease process. Keywords: CTCF, ER stress, IL-6, muscular dystrophy, NF-κB, trinucleotide, cytokine, splicinghttp://www.sciencedirect.com/science/article/pii/S221112471731450X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masayuki Nakamori Kohei Hamanaka James D. Thomas Eric T. Wang Yukiko K. Hayashi Masanori P. Takahashi Maurice S. Swanson Ichizo Nishino Hideki Mochizuki |
spellingShingle |
Masayuki Nakamori Kohei Hamanaka James D. Thomas Eric T. Wang Yukiko K. Hayashi Masanori P. Takahashi Maurice S. Swanson Ichizo Nishino Hideki Mochizuki Aberrant Myokine Signaling in Congenital Myotonic Dystrophy Cell Reports |
author_facet |
Masayuki Nakamori Kohei Hamanaka James D. Thomas Eric T. Wang Yukiko K. Hayashi Masanori P. Takahashi Maurice S. Swanson Ichizo Nishino Hideki Mochizuki |
author_sort |
Masayuki Nakamori |
title |
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy |
title_short |
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy |
title_full |
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy |
title_fullStr |
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy |
title_full_unstemmed |
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy |
title_sort |
aberrant myokine signaling in congenital myotonic dystrophy |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-10-01 |
description |
Summary: 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. : Congenital myotonic dystrophy (CDM) manifests characteristic genetic (very large CTG repeat expansions), epigenetic (CpG hypermethylation upstream of the repeat), and phenotypic (muscle immaturity) features not seen in adult DM. Nakamori et al. find phenotype-genotype and epigenotype correlation in CDM muscle and reveal involvement of the IL-6 myokine signaling pathway in the disease process. Keywords: CTCF, ER stress, IL-6, muscular dystrophy, NF-κB, trinucleotide, cytokine, splicing |
url |
http://www.sciencedirect.com/science/article/pii/S221112471731450X |
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