Aberrant Myokine Signaling in Congenital Myotonic Dystrophy

Cell Reports
Masayuki NakamoriHideki Mochizuki

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.

Citations

Aug 4, 2018·International Journal of Molecular Sciences·Eleonora GuadagninYi-Wen Chen
Dec 18, 2018·Transcription·Emma R HinkleJimena Giudice
Jul 28, 2018·Frontiers in Neurology·Sandra O BrazMário Gomes-Pereira
Jun 13, 2018·Frontiers in Neurology·Laurène M AndréBé Wieringa
Nov 27, 2019·International Journal of Molecular Sciences·Laurène M AndréBé Wieringa
Apr 16, 2019·Frontiers in Physiology·Rosanna Piccirillo
Jul 10, 2020·The Journal of Cell Biology·Gilles MoulayStéphane Vassilopoulos
Nov 7, 2020·Epigenomics·Fabio Coppedè
Nov 16, 2021·Frontiers in Cell and Developmental Biology·Zachary FralishNenad Bursac

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