Zebrafish eye muscles can help fight disease

Muscular dystrophy is a group of diseases in which various proteins in the muscles do not work as they should, either through inherited or spontaneous mutations. This, in turn, causes muscle tissue to break down over time, and patients eventually become wheelchair-bound and often die prematurely because the muscles that help breathing or the heart stop working.

However, the muscles that control eye movements work well throughout the course of the disease, which makes them very interesting to study to try to figure out what strategies they use to survive muscular dystrophy.

the scissors

– In my research, I studied zebrafish eye muscles, which were shown to have the same characteristics in muscular dystrophy as in humans, and then created new disease models. This was done with the help of Crispr/Cas9 gene scissors, says Niels Denhaag.

– By reading gene expression in zebrafish eye muscles, both in healthy fish and those with muscular dystrophy, we have partially succeeded in deciphering how eye muscles deal with these diseases – through regulation of the protein Fhl2.

Healthier muscle fibers

Fhl2 protects the fibers in the eye muscles by preventing them from collapsing and by suppressing abnormal pathological hypertrophy of these muscles. Fhl2 is not found naturally in large portions of the muscles of the body of zebrafish or humans, but through the genetic influence of Fhl2 gene expression, studies have been able to show a significant increase in survival in zebrafish infected with the most lethal type of muscular dystrophy – muscular dystrophy. Duchenne muscle.

In addition to better survival, zebrafish with Duchenne muscular dystrophy—and overexpressing Fhl2—had healthier muscle fibers, significantly better nerve connections and better swimming ability than diseased zebrafish without Fhl2. In addition, fibers that were still broken regenerate faster, leading to better recovery.

Treating people

Overall, our studies suggest that it is possible to use eye muscles as a kind of template for how to deal with living with muscular dystrophy, which has not been proven to the same extent before. We also think this may be a way forward in treating humans, as we have also seen that human eye muscles contain myofibers that express Fhl2. We also believe that we have only scratched the surface of the strategies that eye muscles have to offer, but it is a good step on the way, and proves that this new type of treatment method is possible! says Niels Denhag.

road: Using CRISPR/Cas9 gene scissors to create a number of different models of muscular dystrophy, which are used in the study to study how eye muscles react when these proteins are removed. RNA sequencing of eye muscles and body muscles has been performed to see what differences exist between these tissues under disease conditions. After concluding that Fhl2 was up-regulated in eye muscles, circular DNA was used with the Fhl2 gene linked to the so-called muscle-specific promoter, which was injected into zebrafish with muscular dystrophy. This causes all muscles in the body to express Fhl2, not just the eye muscles, leading to the effects described above.

Niels Denhag He was born in Uppsala but grew up in Fansby, outside Umeå. He studied the biomedical program at Umeå University and then got a job via degree projects in the group of Jonas von Hofstein, before obtaining a PhD in the group of Fatima Pedrosa Domilov.

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