Elevated Levels of Active GSK3β in the Blood of Patients with Myotonic Dystrophy Type 1 Correlate with Muscle Weakness

TL;DR

This study shows that active GSK3β levels in blood correlate with muscle weakness in Myotonic Dystrophy Type 1 patients, suggesting a potential noninvasive biomarker.

Contribution

The study identifies active GSK3β in blood as a potential noninvasive biomarker for muscle weakness in DM1.

Findings

Active GSK3β levels in PBMCs are elevated in CDM1, juvenile DM1, and adult-onset DM1 patients.

Blood levels of active GSK3β correlate with CTG repeat length and muscle weakness severity.

Thrombospondin and TGFβ levels are also elevated in DM1 patients' blood.

Abstract

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the small-molecule inhibitor of GSK3β, tideglusib (TG), reduces DM1 pathology in DM1 cell and mouse models by correcting the GSK3β-CUGBP1 pathway, decreasing the mutant CUG-containing RNA. Respectively, clinical trials using TG showed promising results for patients with congenital DM1 (CDM1). The drug development in DM1 human studies needs specific and noninvasive biomarkers. We examined the blood levels of active GSK3β in different clinical forms of DM1 and found an increase in active GSK3β in the peripheral blood mononuclear cells (PBMCs) in patients with CDM1, juvenile DM1 and adult-onset DM1 vs. unaffected patients. The blood levels of active GSK3β correlate with the length of CTG repeats and severity of muscle weakness. Thrombospondin and TGFβ, linked to the TG-GSK3β pathway in DM1, are also elevated in the DM1 patients’ blood. These findings show that the blood levels of active GSK3β might be developed as a potential noninvasive biomarker of muscle weakness in DM1.

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