Problems in IL-6 Pathway Linked to Severe Symptoms of Congenital Myotonic Dystrophy in Study

Aberrant signaling in the IL-6 pathway, which is involved in muscle cell maturation, contributes to the severe symptoms seen in congenital myotonic dystrophy (CDM) patients, researchers in Japan report.

The study, “Aberrant Myokine Signaling in Congenital Myotonic Dystrophy” published in the journal Cell Reports, also suggests that treatments aimed at regulating the interleukin-6 (IL-6) pathway may be of help to these patients.

Myotonic dystrophy can develop at any age in a person, and has two genetically distinct forms, DM type 1 (DM1) and DM type 2 (DM2). DM1 is caused an expansion of the DNA sequence CTG in the DPMK gene, while DM2 is caused by an expansion of CCTG repeats in the CNBP gene. These mutations lead to the production of toxic RNAs that alter the activity of RNA-splicing proteins.

The process of producing an RNA subtype called messenger RNA (mRNA) from DNA is called transcription. Splicing is a process that turns pre-mRNA into mature mRNA, which are then used to make proteins.

Poorly regulated splicing in muscle cells is known to be a factor in the muscle weakness seen in adults with DM1.

Congenital DM1 (CDM) is a severe disease form of DM1 whose symptoms are evident soon after birth, implying specific processes are involved in this disease — although they are not well understood. Children with CDM have extremely long CTG repeats in the DMPK gene, and the CTG repeats in the DNA are surrounded by high levels of methylation (a process that affects transcription) in areas called CpG islands. Methylation of CpG islands are linked to improper, or dysregulated, with DNA transcription.

The scientists focused on trying to determine “why only expanded CTG repeats in the DMPK and not CCTG repeats in the CNBP gene result in CDM, and how highly methylated CpG sites around the expanded repeats contribute to the disease process, and what causes severe muscle immaturity in CDM,” Masayuki Nakamori, the study’s lead author, said in a press release.

Results showed that the IL-6 myokine signaling pathway is overactive in the muscles of CDM patients. This pathway is known to contribute to muscle cell wasting and atrophy.

Researchers also discovered a correlation between muscle immaturity, high IL-6 expression, high CTG repeat length, and methylation of the CpG islands. As predicted, abnormal CpG methylation was associated with poorly regulated transcription at the repeat site and that led to an increase in toxic RNAs, which in turn increased IL-6.

As the IL-6 pathway is involved in muscle cell maturation and muscle atrophy, results from this study suggest that increased burden of toxic RNAs leads to the severe phenotype of CDM through IL-6 signaling.

These results “support the possibility of treatment for CDM through interventions in IL-6 (the NF-kB) signaling pathways, which have been applied successfully for other diseases, including rheumatoid arthritis,” Hideki Mochizuki, a study co-author, said.