459P Correlation of minimally invasive blood biomarkers with muscle-derived molecular signatures in myotonic dystrophy type 2

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.534
• Main Authors: Kleefeld, F., Hentschel, A., Preusse, C., Schoser, B., Stenzel, W., Roos, A.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.543

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant disorder characterized by a spectrum of systemic manifestations, primarily presenting with proximal muscle weakness, myalgia, myotonia, and muscle atrophy. The underlying pathology involves a CCTG tetranucleotide expansion within the CNBP gene, resulting in an RNA-dominated spliceopathy. DM2 lacks effective treatment options, necessitating a deeper understanding of its pathophysiological mechanisms. In the context of Myotonic dystrophy type 1 (DM1), promising treatment targets, including disturbed mitochondrial metabolism, have emerged. Of note, diverse biomarkers have been identified in DM1, while there is currently no biomarker for DM2. Thus, there are considerable and unaddressed scientific questions in DM2 compared to DM1. We have previously identified mitochondrial abnormalities on both, biochemical and morphological level in muscle biopsy specimens derived from DM2 patients. In this follow-up study, using blood samples obtained from DM2 patients, we aimed to correlate muscle- and blood-derived molecular signatures to (1) investigate multi-systemic aspects of the previously identified mitochondrial alterations and (2) to screen for circulating disease biomarkers of pathophysiological relevance. From EDTA-blood samples obtained from DM2 patients, we isolated white blood cells (WBC) and serum. Both WBC and serum underwent unbiased proteomic analysis by LC-MS/MS, and data was intersected with muscle tissue-derived transcriptomic and proteomic signatures. Using this approach, we identified alterations of several mitochondrial proteins in WBC derived from DM2 patients, thus confirming our results obtained from skeletal muscle specimens and pointing at (multi-)systemic mitochondrial alterations in DM2. Dysregulated proteins were linked to respiratory chain complexes I and III. Other prominently downregulated proteins in WBC were involved in DNA and RNA binding. Prominently upregulated proteins in WBC were linked to protein quality control and splicing, pointing toward compensatory mechanisms in the context of wide-spread, disease-associated mis-splicing events. In addition, we identified several new biomarker candidates in serum samples derived from DM2 patients. In conclusion, DM2 emerges as a disease characterized by systemic mitochondrial dysfunction. This disease-specific molecular signature might serve as a promising treatment target and, in addition, provide new biomarker candidates.