Numerous genes important for muscle-nerve connection identified
Nerves and muscles must work together perfectly for us to move. Researchers at the University of Basel have identified a large number of genes in mice that help maintain the connection between muscle and nerve cells. The study, published in “Nature Communications”, also provides valuable insights for the treatment of currently incurable neuromuscular diseases.
06 March 2025 | Katrin Bühler
Walking, breathing, or writing – these movements would not be possible without our muscles. The instructions are given by the nerves that communicate with the muscles through neuromuscular junctions. Damage to or loss of these connections can lead to neuromuscular diseases, such as muscular dystrophies, or amyotrophic lateral sclerosis (ALS), and is a major contributor to muscle weakness at high age.
But how do muscles maintain their connections to the neurons? This question was addressed by Prof. Markus Rüegg’s team at the Biozentrum of the University of Basel. Using cutting-edge technologies, the researchers have identified numerous genes in mice that maintain a stable and functional connection between nerve cells and muscle fibers. Understanding the underlying molecular mechanisms could help develop effective neuromuscular disease therapies.
The vital role of muscle fibers
Skeletal muscles consist of individual muscle fibers that can reach several centimeters in length. The fusion of many muscle precursor cells forms these fibers. Depending on their length, a muscle fiber can contain hundreds to thousands of nuclei located at the periphery of the muscle fiber. These so-called myonuclei ensure an adequate supply of proteins necessary for muscle growth and contraction.
However, myonuclei near neuromuscular junctions have an additional role. They specialize in forming and maintaining the connection between nerves and muscles. “Using single-nuclei RNA sequencing, we were able to analyze the entire transcriptome – the mRNAs – in individual nuclei at these contact sites,” says first author Alexander Ham. “This showed us which genes are active and which proteins are likely produced.”
Numerous genes ensure a stable connection
The researchers identified more than 450 genes that are specifically active in myonuclei at the site of the neuromuscular junction. For selected genes, they elucidated their specific functions and demonstrated that these genes stabilize the nerve-muscle contact site.
They also showed that nerve cells control which genes are turned on or off in the myonuclei. “Electrical activity of neurons promotes the expression of genes contributing to neuromuscular junction stability,” explains Ham. “Furthermore, various nerve-derived factors involved in the development of the neuromuscular junction affect gene expression.”
Interactive atlas as a valuable resource
The extensive data were integrated into an interactive genetic atlas, providing a valuable resource for scientists worldwide. “In the future, gene therapies could be developed to specifically target the genes that contribute to the stability of the nerve-muscle connection,” says Rüegg. “Most neuromuscular diseases remain incurable. If gene therapies could help preserve or even restore the connections between muscles and nerves, it would be a major step forward. Our work is the first step in identifying such candidate genes.”
Original publication
Ham, A.S., Lin, S., Tse, A. et al.
Single-nuclei sequencing of skeletal muscle reveals subsynaptic-specific transcripts involved in neuromuscular junction maintenance
Nature Communications (2025), doi: 10.1038/s41467-025-57487-1
