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Genethon: Shining light on a key mechanism of Duchenne muscular dystrophy


Following upon the AFM-Téléthon’s recent presentation of the novel studies and biotherapeutic successes in rare genetic diseases, Genethon’s Progressive Muscular Dystrophies team has shed light on a key mechanism of dysfunction in Duchenne muscular dystrophy involving the energy-producing mitochondria in muscle cells.
l’équipe « Dystrophies musculaires progressives » du laboratoire Généthon l’équipe « Dystrophies musculaires progressives » du laboratoire Généthon

After a first article in 2021, Ai Vu Hong, David Israeli, Isabelle Richard and other team members have provided an encore published in October 2022 in Life Science Alliance. In this second work, they explore the role of a group of non-coding RNAs* with genetic roots in the Dlk1-Dio3 (DD) locus in the setting of Duchenne muscular dystrophy (DMD)**.

In their earlier study, the team demonstrated the overexpression of about 20 DD microRNAs -a type of non-coding RNA—in the sera and muscles of patients with DMD. In the most recent one, they experimentally explored the role of that overexpression. The team overexpressed 14 of the DD microRNA in a murine DMD model and measured the effects on muscular activity via transcriptomic analyses. In so doing, the researchers showed that the DD microRNAs act coordinately on mitochondria, the cellular organelles responsible for energy production, by decreasing their activity and increasing oxidative stress. The animal model presented the same muscle dysregulation observed in patients with DMD, in whom the microRNA overexpression occurs as part of the disease.

The DD microRNAs’ action on mitochondrial dysfunction was confirmed in a skeletal muscle cellular model. Specifically, the team reduced the expression of the concerned microRNAs in myotubes (a cellular precursor structure of muscle fibers) created in vitro from iPS cells. The knock-down of those microRNAs indeed led to improvement of mitochondrial activity and in particular of oxidative phosphorylation, the mechanism driving the production of ATP, the cell’s main energy compound. The team also showed the involvement of DD microRNAs in mitochondrial metabolism.

production de microARN DD et l’activité mitochondriale dans un des mécanismes de la myopathie de Duchenne
Visual study summary:
In patients with Duchenne muscular dystrophy (right), there is a permanent state of regeneration in the muscle fibers, which leads to the overexpression of DD microRNAs (small fragments in the image). These latter reduce mitochondrial (kidney-shaped organelle) activity and particularly the oxidative phosphorylation (OxPhos) involved in the production of ATP, the cells primary energy provider.
In healthy individuals (left), DD microRNA production is restrained, leaving the mitochondria unaffected.

A new viewpoint on the mechanisms driving mitochondrial dysfunction


Since the 1970s, faulty calcium regulation has been considered to be the unique driver of muscle energy loss in muscular dystrophies (Science Direct). With their latest work, the Genethon researchers establish a new viewpoint on the mechanisms driving mitochondrial dysfunction and thus muscle energy production in Duchenne muscular dystrophy. Their work has indeed brought to light a more complex supplementary mechanism involving the dysregulation of microRNA expression directly affecting mitochondrial activity and leading to the degeneration of muscle fibers. This notable breakthrough puts novel molecular pathways on the map and thus creates new therapeutic possibilities to explore. This study contributes to Genopole’s health and innovative biotherapies strategic sector.

  • * More on non-coding RNA

    Genes can be thought of as small segments of DNA in the genome that code for the proteins responsible for a wide array of organic functions. However, the end result of a great number of genes is not a protein, but rather any of a range of “non-coding RNAs,” the major biological roles of which are being progressively brought to light. MicroRNAs are a type of non-coding RNA that act particularly on the regulation of gene expression, and thus on adaptation to environmental changes, the development of the organism, cell differentiation, etc.

  • ** More on Duchenne muscular dystrophy

    Duchenne muscular dystrophy is a rare genetic disease causing progressive muscular degeneration. It occurs in about one child in 5,000, usually in boys. In these patients, one of the largest genes in the human genome is mutated, specifically one on the X chromosome that codes for dystrophin, a protein that plays a vital role in muscle fiber support and organization. The abnormal expression of dystrophin leads to progressive degeneration of not only skeletal but also cardiac muscle.

References

Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy

Life Science Alliance Oct 2022, 6 (1)
e202201506; DOI: 10.26508/lsa.202201506

Mitochondrial Calcium Overload: A General Mechanism For Cell-Necrosis In Muscle Diseases

Published: March 27, 1976
DOI: https://doi.org/10.1016/S0140-6736(76)92781-1
https://www.sciencedirect.com/science/article/abs/pii/S0140673676927811

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