Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by multi-system involvement. Affected organ system includes skeletal muscle, heart, gastro-intestinal system and the brain. In this review, we evaluate the evidence for alterations in insulin signaling and their relation to clinical DM1 features. We start by summarizing the molecular pathophysiology of DM1. Next, an overview of normal insulin signaling physiology is given, and evidence for alterations herein in DM1 is presented. Clinically, evidence for involvement of insulin signaling pathways in DM1 is based on the increased incidence of insulin resistance seen in clinical practice and recent trial evidence of beneficial effects of metformin on muscle function. Indirectly, further support may be derived from certain CNS derived symptoms characteristic of DM1, such as obsessive-compulsive behavior features, for which links with altered insulin signaling has been demonstrated in other diseases. At the basic scientific level, several pathophysiological mechanisms that operate in DM1 may compromise normal insulin signaling physiology. The evidence presented here reflects the importance of insulin signaling in relation to clinical features of DM1 and justifies further basic scientific and clinical, therapeutically oriented research.

The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to (a) ascertain if transcriptome changes were associated with increasing disease severity, as measured by the muscle impairment rating scale (MIRS), and (b) establish if these changes in mRNA expression and associated biological pathways were also observed in the Dystrophia Myotonica Biomarker Discovery Initiative (DMBDI) microarray dataset in blood (with equivalent MIRS/DMPK repeat length). The changes in gene expression were compared using a number of complementary pathways, gene ontology and upstream regulator analyses, which suggested that symptom severity in DM1 was linked to transcriptomic alterations in innate and adaptive immunity associated with muscle-wasting. Future studies should explore the role of immunity in DM1 in more detail to assess its relevance to DM1.

Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

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