A heart tube from a healthy fruit fly. Image credit: Meera C Viswanathan (CC BY 4.0)
Myosin is a motor protein that drives the contraction of muscles. Filaments made from myosin molecules slide between filaments of another protein called actin, tugging the edges of the muscle cell inwards. To achieve this, part of each motor protein – called the 'head' – grabs hold of actin and uses energy to pull on the filaments.
Small genetic mutations in the gene for myosin can change the shape of the protein. This can change the way that it interacts with actin, altering the molecular machinery that makes muscles contract. In some cases, gene errors can cause the heart muscle wall to thicken, a condition called hypertrophic cardiomyopathy. Mapping the locations of known mutations revealed 'hot spots' on the myosin protein where these errors are likely to cause disease. These include the part of the molecule that swings the myosin heads, and the heads themselves.
It only takes a change to a single letter in the DNA code to thicken the heart wall, but the impact of each possible change is not yet known. Kronert et al. have now genetically modified fruit flies to give them one of the mutations that causes thickening of the heart wall in humans. The mutation, known as K146N, does not appear in one of the well-known 'hot spots'. The experiments revealed that the mutation causes myosin to remain attached to actin for longer than normal. This increased the amount of force the myosin generated, but slowed down actin movement, causing muscle stiffness. This resulted in less power for every cycle of muscle movement, and caused the muscles to degenerate over time. As a result, the flies were less able to use their wings, and their hearts pumped less well.
Hypertrophic cardiomyopathy can cause death in young adults, particularly competitive athletes. Yet studying the disease in humans is challenging. Recreating myosin mutations in fruit flies provides a way to study hypertrophic cardiomyopathy in the laboratory. In the future, extensions to this technique could allow researchers to examine the impact of other mutations. Models like this one could also allow early testing of new drugs or genetic treatments to repair faulty myosin molecules.
