Zebrafish's eye muscles can provide help against diseases
NEWS
The discovery that the protein Fhl2 is upregulated in the eye muscles in muscular dystrophies, and that it is possible to use Fhl2 to relieve symptoms of muscular dystrophies in muscles other than the eye muscles.
Muscular dystrophies are a group of diseases in which various proteins in the muscles do not function properly, either through inherited or spontaneous mutations. This, in turn, leads to muscle tissue breaking down over time and patients eventually become wheelchair-bound and often die prematurely due to the muscles that help with breathing or the heart stop working. However, the muscles that control the movements of the eye work well all the way through the course of the disease, which makes them highly interesting to study to try to find out what strategies they use to survive muscular dystrophies.
The genetic scissors
“In my research, I have studied the zebrafish's eye muscles, which have been shown to have the same properties in muscular dystrophies as humans, and then generated new disease models with the help of the genetic scissors Crispr/Cas9”, says Nils Dennhag.
“By reading the gene expression in the eye muscles of zebrafish, both healthy and fish with muscular dystrophies, we have partly succeeded in decoding how the eye muscles handle these diseases – through upregulation of the protein Fhl2.”
Healthier muscle fibers
Fhl2 protects the muscle fibers in the eye muscles by preventing they break down, as well as restraining an unnatural pathological enlargement of these. Fhl2 is not found naturally in large parts of the body muscles of zebrafish or humans, but by genetically forcing Fhl2 gene expression here as well, we were able to show a large increase in survival in zebrafish with the most lethal type of muscular dystrophy – Duchenne muscular dystrophy. In addition to better survival, zebrafish with Duchenne muscular dystrophy, but who also had increased expression of Fhl2, had healthier muscle fibers, markedly better innervation and better swimming ability than sick zebrafish without Fhl2. In addition, the fibers that did break down regenerated faster, which led to a better recovery.
Possible treatment method
“Overall, our studies show that it is possible to use the eye muscles as a kind of template for how to cope with living with muscular dystrophies, which has not been demonstrated to the same extent before. We also believe that this may be a way forward for the treatment of humans, as we have also seen that human eye muscles have muscle fibers that express Fhl2. We also believe that we have only scratched the surface of the strategies the eye muscles have to offer, but it is a good step on the way, and shows that this new type of treatment method is possible!” says Nils Dennhag.
Method: We have used the CRISPR/Cas9 genetic scissors to create a number of different models of muscular dystrophies, which are used in the study to study how the eye muscles react when these proteins are removed. We then sequenced RNA from both eye muscles and body muscles to see what differences existed between these tissues under disease conditions. When we found that Fhl2 was upregulated in eye muscles, we used circular DNA with the Fhl2 gene, which is linked to a 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, which led to the effects described above.
Nils Dennhag was born in Uppsala but grew up in Vännäsby outside Umeå. He studied the Biomedicine program at Umeå University and then got a job through degree projects in Jonas von Hofsten's group, before he got a PhD position in Fatima Pedrosa Domellöf's group.
