Abstract
Skeletal muscles are large cells with multiple nuclei that are precisely positioned. The importance of the correct nuclear position is highlighted by the correlation between mispositioned nuclei and muscle disease (Spiro et al., 1966; Gueneau et al., 2009). Myonuclei are generally considered to be equivalent and therefore how far nuclei are from their nearest neighbor is the primary measurement of nuclear positioning. However, skeletal muscles have two specialized cell-cell contacts, the neuromuscular (NMJ) and the myotendinous junction (MTJ). Using these cell-cell contacts as reference points, we have determined that there are at least two distinct populations of myonuclei whose position is uniquely regulated. The post-synaptic myonuclei (PSMs) near the NMJ, and the myonuclei near the myotendinous junction myonuclei (MJMs) have different spacing requirements compared to other myonuclei. The correct positioning of pairs of PSMs depends on the specific action of dynein and kinesin. Positions of the PSMs and MJMs relative to the junctions that define them depend on the KASH-domain protein, Klar. We also found that MJMs are positioned close to the MTJ as a consequence of muscle stretching. Our study defines for the first time that nuclei in skeletal muscles are not all equally positioned, and that subsets of distinct myonuclei have specialized rules that dictate their spacing.
Highlights
Syncytia are multinucleated cells that typically exist as embryonic developmental transitions, such as the fly syncytial blastoderm, or as a terminal differentiated specialized cell, including skeletal muscles, osteoclasts, or placenta
We measured the position of nuclei relative to two specialized cell-cell contacts, the neuromuscular junction (NMJ) and the myotendinous junction (MTJ)
To determine whether the nuclei nearest the NMJ had a distinct spacing compared to other nuclei in the muscle fiber, we measured the distances between each nucleus and its nearest neighbor on the A-P axis because nuclei were positioned in two parallel rows on the A-P axis
Summary
Syncytia are multinucleated cells that typically exist as embryonic developmental transitions, such as the fly syncytial blastoderm, or as a terminal differentiated specialized cell, including skeletal muscles, osteoclasts, or placenta. One fundamental question is whether all of the nuclei in a multinucleated cell are functionally equivalent. Individual nuclei undergo several nuclear movements that result in peripherally positioned nuclei evenly spread along the surface of the myofiber. The regular positioning of nuclei, and the movements that generate this pattern, are conserved from Drosophila to mammals (Folker and Baylies, 2013; Roman and Gomes, 2017). The evolutionary conservation suggests that myonuclear movements are critical to muscle development and function.
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