NEW INSIGHTS INTO CELLULAR FUNCTIONS: O.10The nuclear-cytoskeleton connection and nuclear positioning during muscle formation

Abstract

Muscle cells are characterized by the presence of multiple nuclei evenly spaced under the plasma membrane. Whether this particular arrangement is required for muscle function is still under debate. Nonetheless, several muscular diseases are characterized by abnormal nuclear positioning, such as centronuclear myopathies, titinopathies and desminopathies or due to mutations of nuclear envelope proteins known to be involved in nuclear movement in other systems. The position of nuclei could be important for proper distribution of mRNA and proteins in such large cells. We have, since several years, investigated the mechanisms controlling three of the four different and successive nuclear movements occurring during myofiber formation through live imaging. We have developed cell systems which can achieve myofiber maturation, with peripheral nuclei and presence of triads and sarcomeres. By screening the effect of different molecular motors deletion, we have identified several microtubule-associated motors implicated at different levels on nuclear movement and positioning. We have established the connection between the nucleus and the cytoskeleton to be decisive for proper nuclear positioning. In particular, nesprin-1, a protein mutated in congenital muscular dystrophy, is required for the reorganization of the microtubule cytoskeleton during the differentiation of muscle cells and the subsequent nuclear movements. Anchored to the nuclear envelope, nesprin-1 is part of the LINC complex, making the link between the cytoskeleton and the lamins inside the nucleus. Our research using in vitro systems recapitulates in vivo observations and allow the study of the impact of mutations found in muscular diseases on nuclear positioning in muscle cells.