A novel embryonic zebrafish model to replace mammals in the study of 3-hydroxyacyl CoA dehydratase 1-associated muscle disorders

Why did we fund this fellowship?

This award aims to replace the use of dogs and mice in studies of congenital muscle disorders by developing an early stage zebrafish embryo model deficient in HACD1.

Mutations in the HACD1 gene cause congenital myopathies in humans and dogs. The gene encodes an enzyme responsible for very long chain fatty acid (VLCFA) biosynthesis in skeletal muscles. HACD1 and VLCFA are thought to play a role in normal myogenesis, muscle repair and maintenance of the cell membrane systems that are essential for excitation-contraction coupling. Transgenic mice and Labrador retrievers are used in the research with the animals experiencing muscle weakness and atrophy, decreased muscle tone, weight loss and progressive exercise intolerance, consistent with the clinical signs observed in patients. The zebrafish presents an alternative model system as mature muscle is present three days after fertilisation. At this early stage the embryos are not considered capable of suffering and they therefore provide a replacement for the use of other animals.

Dr Rhiannon Morgan undertook an extensive characterisation of the zebrafish HACD1 homolog during her PhD studies, including demonstrating that mutant F0 embryos show muscle abnormalities. During the Fellowship, Rhiannon will establish and characterise two zebrafish lines with clinically-relevant mutations in the HACD1 active site, helping to build confidence in the use of the model instead of dogs or mice for studying the gene in normal muscle function and disease. She will develop skills in gene editing, muscle electrophysiology and analysis of the lipidomic data.