Key result
Upregulation of the IL-6 myokine signaling pathway, driven by expanded CTG repeats and aberrant CpG methylation, correlates with muscle fiber immaturity in congenital myotonic dystrophy.
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.
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Nakamori et al. (2017) studied Congenital myotonic dystrophy. Aberrant IL-6 myokine signaling and CpG methylation was evaluated on Muscle fiber immaturity and transcriptional dysregulation. Upregulation of the IL-6 myokine signaling pathway, driven by expanded CTG repeats and aberrant CpG methylation, correlates with muscle fiber immaturity in congenital myotonic dystrophy.
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