Exploring myonuclear heterogeneity and compartmentalization of muscle fiber is important for understanding the pathophysiological impact of muscle diseases.

by Dr. Amalia Stantzou

Publication:
Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells
Minchul Kim et al.
Nature Communications 2020 Dec
https://pubmed.ncbi.nlm.nih.gov/33311457/

The data presented in the manuscript by Minchul Kim and colleagues highlights the presence of myonuclear heterogeneity and compartmentalization in the muscle fibers independently to fiber type diversity.

The authors performed single-nucleus RNA sequencing (snRNAseq) in FACS-sorted genetically labelled myonuclei isolated from fibers in homeostasis and during regeneration as well as from dystrophic fibers from mdx mice. In addition to this technique to identify myonuclear populations, they also performed fluorescence in situ hybridization (FISH) allowing them to identify the position of the myonuclear populations within the fibers.

In uninjured and in regenerating fibers, they identified different nuclear subtypes, such as the expected ones at the neuromuscular and myotendinous junctions (NMJ and MTJ), and they are the first to describe the existence of two distinct MTJ myonuclear populations, perimysial myonuclei, as well as subpopulations which were not associated with distinctive anatomical features of the fibers but were rather dispersed along the myofibers. They provide evidence that this transcriptional heterogeneity is dynamic as shown in different stages of regeneration.

Importantly, when looking at the mdx model for DMD the authors found that myonuclear compartmentalization is lost and identified molecular signatures which could provide a quantitative evaluation of muscle damage.

This study shows that myonuclear heterogeneity could certainly be involved to bring about specific patterns of affected muscles in muscle diseases. Therefore, snRNAseq techniques combined with single molecule FISH are certainly to become an important methodology in pathophysiological research in myology.

About the Author

I obtained my PhD in South Korea, working on the Hippo signaling pathway. After a short post-doc in the States, I joined Carmen Birchmeier's lab in Berlin where I became interested in the peculiar properties of myofibers, imposed by their syncytial nature. This perspective led me to the recent work, which characterized single-nucleus transcriptomes of myofiber. Starting next February, I will launch my own group at the IGBMC in Strasbourg, France.

About the Reviewer

I obtained my binational French-German PhD, in the MyoGrad progam, in 2015 where I studied the role of BMP signaling in postnatal muscle development. During my postdoc in the team of Prof. Helge Amthor at the University of Versailles Saint-Quentin-en-Yvelines I have been studying dystrophin restoration following antisense oligonucleotide treatments in dystrophic reporter mouse models.