Over 40% of the human body is made up of skeletal muscle, which are essential for breathing, and for movement. Skeletal muscles are composed of numerous cells called muscle fibres. Within the muscle fibres, two main proteins called myosin and actin are organised into thick and thin filaments respectively, and these filaments have highly precise, lengths. These filaments are organised into muscle sarcomeres, which are in turn organised in long linear arrays from one end of the muscle fibre to the other. The interaction of myosin with actin in each muscle sarcomere drives a small shortening of each sarcomere (known as a contraction), which is summed along the muscle fibre, to drive muscle shortening, which in turn drives movement. Genetic alterations to the genes that encode part of the myosin molecule mean that a faulty (or mutant) protein is made, and this leads to severe muscle weakness in patients, in a type of disease known as myosinopathies. We do not understand how these faulty (or mutant) myosin proteins cause skeletal muscle weakness. Our research will help us to obtain a new understanding of how faulty myosin proteins cause myosinopathies. We will be able to test how mutations affect the molecular structure of the myosin, how this affects its ability to form precisely built filaments, and how this then results in changes to muscle structure, leading to muscle weakness. Our approaches will range from investigating individual fragments of myosin to investigating the organisation and properties of myosin in intact human patient samples to enable us to obtain a deep understanding. This new knowledge will not only greatly advance our understanding of myosinopathies, but, most importantly, suggest pharmacological targets that may be exploited for effective therapeutic interventions.