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.

日本語要旨:

先天性筋強直性ジストロフィー(CDM)は、成人DMでは見られない筋線維の未成熟を特徴とする。本論文ではそのメカニズムを解明した。CDMではCTGリピートサイズが非常に大きく異常なCpGメチル化がリピート周囲での転写調節不全と関連していた。また異常なCpGメチル化によりRNA毒性が増大し、筋細胞の成熟や萎縮に関与するインターロイキン-6 (IL-6)ミオカインシグナル伝達経路をupregulateさせていた。本論文により、IL-6の増加が重篤なCDM表現型に寄与していることが示された。