Every muscle in the human body—from those that move limbs to the one that pumps blood—depends on a microscopic scaffold called the sarcomere, and this project will investigate how that scaffold goes wrong in inherited muscle diseases. Mutations in titin, the largest protein in the human body, are a common cause of severe muscle disorders, especially in children. These mutations produce defective proteins that can clump together and disrupt normal muscle function, but the cell’s own quality-control systems for catching and removing such faulty proteins remain poorly understood. This research focuses on the M-band, a structure within the sarcomere that appears to sense mechanical stress and coordinate protein turnover. The team will study how missense mutations in titin and the related protein obscurin interfere with this quality-control machinery. The work is fundamental science: it aims to reveal the basic mechanisms by which sarcomeres regulate their own repair and replacement. If successful, it will explain why specific genetic defects cause muscle wasting and weakness, laying the groundwork for future therapies that target protein quality control rather than just managing symptoms.
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The function of striated muscles, so called because of their highly regular striation pattern when viewed in a microscope, is crucial for the movement of our body and heart muscles. These stripes are formed from the repetitive arrangements of molecular machines, called sarcomeres that generate force and movement. In the sarcomere, three systems of molecular filaments are working together: actin filaments, which are held together at the Z-disk, myosin filaments, held together at the M-band, and the giant protein filament titin, which links the actin and myosin filaments. Muscle responds rapidly to changes in use, with disuse leading to muscle loss (called atrophy) and exercise leading to muscle growth (called hypertrophy). These processes need to be constantly balanced, and are linked in a coordinated way to those controlling muscle repair by making new proteins for sarcomere repair and replacement of other unwanted or damaged components of the cell. Signals controlling muscle protein turnover are emerging to originate at the M-band and the Z-disk. These structures contain proteins that can sense mechanical stress and control the activity of the protein degradation machinery. Many of these proteins, however, remain enigmatic or haven't even been discovered, and often even their most fundamental functions have not been elucidated. Yet, when the integration of the M-band as a machinery combining structural, mechanical and communication functions is disrupted by genetic defects, severe muscle diseases are the result. This study will shed light on the compositions and regulation of the M-band, its role as a regulator of proteostasis, and why mutations in two of the giant proteins that are involved in its assembly, titin and obscurin, can lead to muscle disease. Inherited defects in the giant muscle protein titin, the largest in the human body, are increasingly identified as common causes of a broad range of muscle diseases. Many of these mutations cause defective proteins that the muscle cell would need to prevent from behaving abnormally by clumping together and interfering with normal function, which may be a major disease mechanism. We will study the impact of code-changing "missense" mutations in titin on the ability of the cell to cope with defective proteins, called protein quality control. The findings will help us to understand the basic mechanisms of how sarcomeres regulate sarcomere quality control, and how this fundamental mechanism is perturbed in severe inherited myopathies affecting mainly children.
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