Muscles contract so that we can move our bodies, breathe, swallow etc. Several muscle conditions are the result of changes in the genes and proteins involved in muscle contraction. Drugs that regulate muscle contraction could potentially be used in the treatment of some of these conditions.
Muscle contractions and treating the heart
Muscle contraction involves long filaments (like strings or wires) of two proteins called actin and myosin, sliding over each other. Myosin, an ancient protein whose origin predates the evolution of animal life, acts as a motor that can bind to, and pull itself along, actin filaments.
A drug called Omecamtiv Mecarbil (OM) that regulates myosin activity, has undergone clinical trials. However, the drug's effect is specific to a form of myosin that is found in the heart muscle, so its use may be limited to conditions such as heart failure. The drug has little effect on the main form of myosin found in the skeletal muscles – the muscles that make up a large part of our body mass and are responsible for movement.
Research to understand myosin drug specificity
A recent study funded by Muscular Dystrophy UK, led by Dr Arianna Fornili at Queen Mary University of London, aimed to understand why OM acts specifically on heart myosin and not on skeletal muscle myosin. The researchers took a close look at a pocket-shaped cavity in the myosin protein into which the drug molecule attaches itself. Interestingly, there are only small differences between myosin in the heart and myosin in skeletal muscle.
The study used computer processes, called algorithms, to predict how the tiniest parts of the myosin protein would interact with the OM drug molecule. Drugs and proteins will organise themselves, based on the attractive and repulsive forces in the chemical groups they each carry.
The precise arrangement of OM bound to heart myosin had already been discovered using a method called X-ray crystallography. The team used that existing structure as a template to predict the structure of OM bound to the skeletal muscle myosin. They found that the pocket-shaped cavity of the skeletal muscle myosin was larger and differently shaped than that of the heart myosin. This resulted in OM binding less strongly within it.
What does this mean for possible treatments?
This work could enable the design of drugs to target skeletal muscle myosin. These drugs could be used to regulate skeletal muscle contraction and could be explored as possible treatments for muscle conditions where myosin function is disrupted, such as MYH2 myopathy, nemaline myopathy, and certain congenital myopathies.
‘What’s new in research’ is our monthly blog series featuring recent advancements in research into muscle-wasting conditions. Each month, we choose a research article that will be summarised for you by our research communications volunteers, all of whom have backgrounds in various fields of research.
This piece is written by Bill Duddy. Bill is a lecturer in the neuromuscular research team at Ulster University School of Medicine. He lost his brother to Duchenne muscular dystrophy, has devoted his career to the understanding and treatment of neuromuscular conditions, and enjoys explaining science.