Muscle Disease and Development

Muscular dystrophy is the collective name for a group of genetic diseases that cause the progressive break down of muscle in the body. The diseases lead to weakness and subsequent loss of mobility. The heart, diaphragm, and gastrointestinal muscle may also be affected. Although the distinct kinds of muscular dystrophy involve different genes, for the most part the muscle loss is due to the death of damaged muscle cells. There is no known cure and treatment is limited. We can use zebrafish models to investigate the genetic causes of muscular dystrophy and try to determine what changes are occurring in the cells when certain genes are mutated.
Duchenne Muscular Dystrophy (DMD) DMD is caused by a defect in the gene coding for dystrophin. Dystrophin is a structural protein that provides support in the muscle cells by anchoring the internal scaffolding of the cell (called the cytoskeleton) to the cell membrane. When the dystrophin gene is mutated the resulting protein is no longer fully functional. Over time the scaffolding pulls away from the cell membrane, causing the cell to collapse and die. This leads to the muscle wasting characteristics of DMD. We can model DMD and other muscular dystrophies by looking at fish that carry similar mutations to those found in humans. One such mutant is royal vegas casino called sapje and has a mutation in the dystrophin gene. Like in the human patients the muscle in the fish degenerates and dies. We can learn about how dystrophin functions in cells and in the whole organism using mutants such as sapje. We can also investigate possible treatments for the disease by screening potential drugs on the fish and looking for ‘rescue’ of the muscle damage.
Normal muscle development and function Part of understanding diseases such as muscular dystrophy requires us to know how muscle normally develops in an embryo and how it functions in a living organism. Zebrafish have been used extensively to understand the development of muscle from single cells (called myocytes) into large bundles of contractile muscle fibres, that allow a fish to swim or you and I to walk and run (or swim if we really want).
Muscle fusion To make large muscle fibres many single celled myocytes must fuse together to create what is called a syncytium, which may consist of thousands of individual cells. Normally a cell has one nucleus, but a syncytial cell has many nuclei, each contributed by the component myocytes. The syncytium is important as it allows coordinated contraction across the whole muscle. Muscles don’t only fuse during embryogenesis. When muscle is damaged, either through injury or normal wear and tear (think of how your muscle ache after lots of exercise), new muscle cells are able to fuse with the existing muscles to repair them.
In this image you can see muscle cells before, during and after fusion. Before fusion there is a single nucleus (the red dot) in each cell. The edge of each cell (the membrane) is labelled in green. During fusion there is a mix of cells with one or more nuclei. After fusion most cells have at least three nuclei. A single cell is highlighted in each image.

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