Identification of a new mechanism underlying muscle pathology in DM1

Researchers from the Repeat Expansions & Myotonic Dystrophy (REDs) team in the Center of Research in Myology at the Institute, whose work focuses on type 1 myotonic dystrophy (DM1 or Steinert disease), have just published an article in Nature Communications, in collaboration with international teams*, highlighting a mechanism whereby muscle stem cells fuse with existing muscle fibres, thereby shedding new light on the origin of the central nuclei frequently observed in patients’ muscles. An interview with Frédérique Rau and Denis Furling who led this work.

In what context did you carry out this research, and what was its objective?

Steinert disease, one of the most common neuromuscular disorders in adults, is caused by an abnormal expansion of CTG repeats in the DMPK gene. This abnormality leads, in particular, to the loss of function of MBNL proteins, which play an essential role in RNAmacromolécule constituée d’une seule chaîne de nucléotides (simple brin) résultant de la transcription (copie) de l’ADN. maturation. In skeletal muscles affected by DM1, nuclei are frequently observed at the centre of muscle fibres, whereas they are usually found at the periphery. These central nuclei are generally associated with a process of muscle degeneration and regeneration; however, in DM1, their accumulation is observed despite relatively limited signs of fibre necrosis and inflammationRéaction non spécifique suscitée par un agent pathogène..

What methods did you use and what results did you obtain?

We combined small non-coding RNA sequencing (snRNA-seq) from muscle biopsies taken from patients with the study of a mouse model in which MBNL proteins are specifically depleted in mature muscle fibres.

Transcriptomic analysis of individual nuclei from human muscles affected by DM1 revealed an increase in activated muscle stem cells and myonuclear populations exhibiting intermediate transcriptional profiles. These populations are characterised in particular by high expression of DMPK and the presence of markers associated with muscle stem cells, suggesting the existence of nuclei exhibiting immature characteristics.

In adult mice, the specific depletion of MBNL proteins in mature muscle fibres reproduced the main characteristics of DM1: myotonia, reduced specific strength, alternative splicing abnormalities, and the presence of central nuclei. Analysis of the nuclei by snRNA-seq also revealed the emergence of immature nuclear populations. The results indicate that these populations arise in part from the activation and fusion of muscle stem cells with existing fibres in the absence of major signs of necrosis.

What conclusions did you draw from this?

These results highlight an active process of muscle remodelling in DM1. In particular, the loss of function of MBNL proteins in muscle fibres promotes the activation of muscle stem cells and their fusion with existing fibres, thereby contributing to the accumulation of central nuclei.

What are the prospects for the future?

The next step will be to gain a better understanding of the role played by the abnormal expansion of CTG repeats in the muscular abnormalities observed in DM1, including the muscle remodelling that occurs as the disease progresses and the formation of new nuclei within muscle fibres. It will be essential to distinguish between effects linked to the mutationModification soudaine et transmissible du matériel génétique. Elle peut être spontanée ou induite par des agents dits » mutagènes » (radiations, produits toxiques,…). itself and those resulting from the loss of function of MBNL proteins in order to better characterise the molecular mechanisms underlying muscle remodelling in this disease.

*The research was carried out in collaboration with researchers from the Friedrich Baur Institute / Department of Neurology, LMU Klinikum in Munich, and the National Centre for Neurology and Psychiatry in Tokyo, in collaboration with other institutions.