Sarcomere proteostasis in titinopathies

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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.