ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Ariany Oliveira-Santos is first author on ‘Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy’, published in DMM. Ariany is a postdoctoral researcher in the lab of Dean Burkin at the University of Nevada, Reno, NV, USA, investigating muscle biology and the development of new therapeutics for muscle diseases, particularly muscular dystrophies.
Ariany Oliveira-Santos
How would you explain the main findings of your paper to non-scientific family and friends?
Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) affects around 0.5 in 100,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene, which results in the loss of laminin-α2 protein. The lack of laminin-α2 results in impaired muscle repair and muscle loss. LAMA2-CMD patients exhibit skeletal muscle weakness at a young age and die prematurely. We found that an important metabolic pathway involved in muscle growth and waste is dysregulated in the skeletal muscles of a mouse model of the disease. Vemurafenib, an FDA-approved drug, regulated this metabolic pathway and improved muscle histopathology in the LAMA2-CMD mouse model. However, the improvements observed were insufficient to improve muscle function, suggesting that vemurafenib alone is inefficient in restoring muscle function.
“We found that an important metabolic pathway involved in muscle growth and waste is dysregulated in the skeletal muscles of a mouse model of [laminin-α2-related congenital muscular dystrophy].”
What are the potential implications of these results for your field of research?
This study identifies a new metabolic pathway that is dysregulated in the skeletal muscles of a mouse model of LAMA2-CMD and provides important information showing that the regulation of this pathway improves muscle histopathology but does not restore muscle function. So, new therapeutics should be able to regulate other signaling pathways besides the mTORC1 pathway, which could result in muscle function improvement.
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
The animal model we used, the dyW−/− mouse model, is a severe model of the disease and presents low levels of truncated laminin-α2 chain, which represents well a group of patients with LAMA2-CMD. However, mouse models do not completely recapitulate human diseases, and potential differences in the mechanisms of the disease in the mouse models and human patients should always be accounted for and the data should be validated with human samples when possible.
Expression of dystrophin (red) and embryonic myosin (green) showing newly formed muscle fibers in the skeletal muscle of dyW−/− mouse.
Expression of dystrophin (red) and embryonic myosin (green) showing newly formed muscle fibers in the skeletal muscle of dyW−/− mouse.
What has surprised you the most while conducting your research?
The mTORC1 signaling pathway is a classic hypertrophic pathway contributing to muscle growth. The fact that sustained activation of that pathway results in the opposite effect leading to muscle atrophy and muscle loss in the dyW−/− mouse model of LAMA2-CMD is very interesting and brings our attention to the fact that a given molecule can have different effects on different conditions.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
Developing a therapy capable of improving muscle function in a very severe form of muscular dystrophy, such as LAMA2-CMD, is definitely the biggest challenge in the LAMA2-CMD research field.
What changes do you think could improve the professional lives of scientists?
Funding is a critical aspect of the professional life of a scientist, especially for young scientists trying to become independent researchers. Additional funding opportunities for young scientists would be essential to improve the professional lives of those scientists.
What's next for you?
I will continue developing medical research in the muscular dystrophy field focusing on understanding the disease mechanisms and developing therapies for muscular dystrophy.
Ariany Oliveira-Santos’s contact details: Department of Pharmacology, University of Nevada Reno, School of Medicine, Center for Molecular Medicine, Reno, NV 89557, USA.
E-mail: [email protected]
