The Saguenay-Lac-Saint-Jean region houses a scientific paradox: a rare neuromuscular disease is surprisingly frequent. Type 1 myotonic dystrophy (DM1), which generally affects one person in 8000 in the world, affects approximately one in 475 people here. This exceptional concentration, due to a phenomenon called the founding effect, transforms the region into a single field of study for researchers.
A research team led by Professor Nicolas Dumont, from the Rehabilitation School of the University of Montreal, has been busy having better understanding the disease for a few years in order to find avenues for treatment. Within this team, we find the postdoctoralist Pauline Garcia and Maya Sottolichio, second-year student in the Department of Microbiology, Infectiology and Immunology, who will continue this work at the Azrieli Research Center in CHU Sainte-Justine.
The DM1 is a hereditary disease attributable to a mutation in a gene called DMPK, which disrupts muscle function and causes progressive atrophy. It can affect different muscles, including diaphragm which is essential for breathing. The severity of the disease depends in part on the size of the expansion of genetic mutation: the greater this expansion, the more severe the symptoms.
It is thanks to a provincial collaboration and access to a biofing of muscle fabrics – established by researcher Élise Duchesne of Laval University – that the team can work with human biopsies. These small fragments of muscles, often taken from the quadriceps of patients at different stages of the disease, are at the center of the study.
When cells tell their story
Pauline Garcia
Credit: Martin Lasalle
In their laboratory, Pauline Garcia and Maya Sottolichio conduct a series of experiences to observe the differences between healthy and sick cells. A question guides them: what, at the cellular level, prevents muscles from repairing themselves normally in people with DM1?
“We start by cultivating the extracted cells from biopsies,” says Pauline Garcia. “Then, they are proliferated to have a sufficient quantity and then analyze their metabolism thanks to different tests.”
One of the key tools of this study phase is a device called Seahorse, which measures oxygen consumption of mitochondria, “energy central” cells. If their functioning is disturbed, this could explain muscle weakness.
Using techniques such as immunofluorescence, researchers can also visualize proteins and nuclei inside muscle fibers, which allows them to compare the activity and structure of sick cells to those of healthy cells.
Transgenic mice to therapeutic hope
Maya Sottelichio
Credit: Martin Lasalle
In parallel with human cell work, the team works with a murin model – a genetically modified mouse to reproduce the characteristics of the DM1. In this transgenic mouse, researchers can cause muscle lesions and observe how cells react to different therapeutic agents. “The idea is to understand the mechanisms behind deregulation,” says Pauline Garcia. Once they are identified, you can test substances to try to correct these faults. ”
“This strategy in several stages – human observation, validation in mice, then experimentation with treatments – is rigorous and essential,” adds the postdoctoral party. It makes it possible to build a bridge between understanding the molecular mechanisms and the identification of potential therapies. ” Ultimately, this could conduct clinical trials in humans, but before, the therapeutic targets must be validated and ensure their effectiveness on preclinical models.
The project is a logical sequence of the team’s recent advances, published Nature Communications, which has revealed a new mechanism involved in the disease as well as a blood biomarker correlated with the severity of the symptoms. These results open the way to a future treatment, but the path remains long.
Science, patience et passion
In this type of research, every detail counts. The basic hypothesis, according to which sick muscle cells proliferate less quickly, seems to be confirmed, but it remains to be determined precisely where and how the process is disturbed. For Maya Sottolichio, who soon began his last year of baccalaureate, this internship is much more than just initiation to research.
“It is motivating to know that we are working on something that could really change lives, especially in a region like Saguenay where the disease is so present,” she said with enthusiasm.
Pauline Garcia recalls that it is important to talk about DM1 as much as other more publicized diseases, such as Duchenne’s muscular dystrophy (DMD). “The DMD attracts a lot of attention, but the DM1 is more frequent in certain regions of Quebec and deserves to be dwelling,” she concludes.
