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Positioning the nucleus for cell migration and muscle fiber function

Final Report Summary - PHONICS (Positioning the nucleus for cell migration and muscle fiber function)

Cells are highly compartmentalized structures and the nucleus is the biggest compartment within cells. The position of the nucleus inside cells is important for multiple activities of cells and tissues such as fertilization, formation of different organs and is mis-regulated in several disorders. Thus, understanding how cells move their nuclei inside cells and the importance for nuclear position is relevant in multiple contexts. In this project we studied how cells position their nucleus during cell migration and during skeletal muscle formation. Skeletal muscle fibers are particularly interesting because they have multiple nuclei and their nuclei are found in specific places within these giant cells. In a mature myofiber, most nuclei are found at the periphery of the myofiber whereas a subset of nuclei are found at the site where the muscle cells contact with the motor neurons (neuromuscular junction) and where the muscle cell contacts with the tendon (myotendinous junction). Furthermore, multiple muscle disorders are associated with mispositioned nuclei in muscle cells, suggesting a role for nuclear positioning in muscle function.

During this project we studied how the cell nucleus is moved and positioned in migrating cells and in muscle cells. We also studied how nuclear positioning is affected in different muscle disorders. During cell migration we previously found that the nucleus is positioning away from the front of the cell. This movement occurs because the actin cytoskeleton connects and moves the nucleus actively. We now found that the organization of multiple organelles in the cytoplasm are also important for the actin cytoskeleton to move the nucleus.

In skeletal muscle formation, the nucleus moves to the periphery of the muscle fiber. During this project we found how this process occurs. We found that the myofibrils, which are contractile rods responsible for muscle contraction, surround the centrally located nucleus and squeeze the nucleus to the periphery of the myofiber. We also found that the stiffness of the nucleus is important for the movement to the periphery. If nuclei are too soft or too stiff, they do not move to the periphery. Finally, we also found that specific isoforms of actin and actin nucleators (Arp2/3 complex) are important for nuclear movement to the periphery. This work also describes how nuclear movement is affected in some muscle disorder and can be de basis for the development of innovative therapies.

Finally, we also found how the microtubule cytoskeleton is attached to the nucleus in skeletal muscle cells and how this mechanical link is disrupted in early onset myopathies. The connection of the cytoskeleton with the nucleus can therefore be a novel therapeutic target for these disorders.