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# Nuclei reprogramming during muscle denervation

Sabrina Batonnet-Pichon, Stéphanie Backer, David Vodinh, Edgar Jauliac, Pascal Maire, Iryna Pirozhkova

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## ► To cite this version:

Sabrina Batonnet-Pichon, Stéphanie Backer, David Vodinh, Edgar Jauliac, Pascal Maire, et al.. Nuclei reprogramming during muscle denervation. At the crossroads of cellular plasticity, reproduction and microbiology, Apr 2024, Dourdan, France. hal-05045425

HAL Id: hal-05045425

https://hal.science/hal-05045425v1

Submitted on 28 Apr 2025

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Institut Cochin Conference

AT THE CROSSROADS
OF CELLULAR PLASTICITY,
REPRODUCTION AND MICROBIOLOGY

23-24 April 2024

Club Belambra de Dourdan "Le Normont"

Organisation committee : Marina Morel, Frédérique Verdier, Romain Fontaine and Sarah Gallois-Montbrun

Organisation of social events : Ludivine Royer, Carmen Al-Youssef and Juliette Desforges

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# Nuclei reprogramming during muscle denervation

Sabrina PICHON, Stephanie BACKER, David VODINH, Edgar JAULIAC, Pascal MAIRE and Iryna PIROZHKOVA

Our working group is devoted to the exploration of "Muscle and Motor Neuron: A Peer-to-Peer Dialogue," with a particular emphasis on nuclear reprogramming during muscle denervation. This investigation is integral to our broader team project, "Neuromuscular Development, Genetics, and Pathophysiology."

Previous studies conducted by our team have revealed coordinated expression patterns along innervated adult myofibers, indicating a shared regulatory mechanism for gene expression. Additionally, various murine models have been developed to mimic different forms of denervation, tenotomy and muscle mass overload (Figure 1).

Alongside traditional inflammation markers, the activation of transposable elements, such as long interspersed nuclear elements (LINE) elements and human endogenous retroviruses (HERV), has been observed during the progression of neurodegenerative diseases, with some evidence suggesting correlation with disease severity. HERVs represent remnants of ancient viral infections integrated into the human genome over evolutionary time. When activated, ERVs generate transcripts, and the most recent among them retain the capacity to produce viral-like particles. Additionally, they can interact with transcription factors and influence immune response modulation.

Adult myofibers harbor diverse classes of myonuclei, encompassing those localized at the predominant body myonuclei, myotendinous junctions and neuromuscular junctions that communicate with motor neurons, Muscle-motor neuron communication can occur through either anterograde or retrograde pathways. In many studies it has been shown that fast type myofibers are first involved in aging, neurodegeneration and other muscular diseases. Despite understanding slow motor neuron-muscle signaling, the pathways governing fast muscle-specific programs remain elusive.

Our primary focus is on deciphering the NMJ's role in skeletal muscle denervation events and uncovering the associated signaling cascades. Our research approach encompasses bioinformatics including machine learning methodologies to analyze denervation-induced myonuclear reprogramming (Figure 2). We also optimize muscle cell culture systems in both 2D and 3D environments, utilizing coculture techniques to replicate myofiber maturation ex vivo.

Furthermore, we integrate cellular models derived from individuals with motor neuropathies such as Amyotrophic lateral sclerosis to gain insights into pathological motor neuron-muscle interactions. From a clinical perspective, we will employ an *in vitro* cell model to screen genes responsive to NMJ blockage or denervation in muscle cells. Promising genes identified through this screening process will be fast-tracked for the development of gene therapy strategies targeting rare neurodegenerative disorders characterized by NMJ degeneration. Our proposed therapeutic approach entails gene therapy mediated by adeno-associated virus (AAV)-derived vectors.
Overall, this multidisciplinary approach aims to elucidate the complex interaction between motor neurons and skeletal muscle during denervation events. The ultimate goal is to advance therapeutic interventions for neurodegenerative disorders characterized by NMJ degeneration, offering thereby potential relief to individuals affected by these debilitating conditions.

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Endogenous Retroviruses (ERVs): New Targets for Muscle Denervation.</figcaption></figure>

The single-nuclei snRNA-seq and snATAC-seq data of murine muscle tissues were generated by our team (GSE150065 and unpublished datasets) and integrated with open access datasets (GSE162307, GSE156498, GSE147127). The expression of genes containing ERVs is specifically upregulated in denervation and overload. Mouse models: RGN, regeneration; OV, overload; DMD, Duchenne muscular dystrophy; P-Acute-Den, plantaris acute denervation (7 days); T-Acute-Den, tibialis acute denervation (7 days); T-Chronic-Den, tibialis congenital denervation; E14, back muscles from the E14 embryonic stage; Slow, Soleus muscles (healthy muscles); Fast, tibialis, plantaris, and EDL muscles (healthy muscles).

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Exploring Motor Neuron-Muscle Communication Subtypes Using a Bioinformatics Approach</figcaption></figure>