Opposing microtubule motors drive robust nuclear dynamics in developing muscle cells

Advance Online Publication May 23, 2012 doi: 10.1242/?jcs.108688 Meredith H. Wilson and Erika L. F. Holzbaur*?*Corresponding author: Erika Holzbaur, Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085. T: (215) 573-3257, F: (215) 573-5851, Email: holzbaur{at}mail.med.upenn.eduDynamic interactions with the cytoskeleton drive the movement and positioning of nuclei in many cell types. During muscle cell development, myoblasts fuse to form syncytial myofibers with nuclei positioned regularly along the length of the cell. Nuclear translocation in developing myotubes requires microtubules, but the mechanisms involved have not been elucidated. We find that as nuclei actively translocate through the cell, they rotate in three-dimensions. The nuclear envelope, nucleoli, and chromocenters within the nucleus rotate together as a unit. Both translocation and rotation require an intact microtubule cytoskeleton, which forms a dynamic bipolar network around nuclei. The plus- and minus-end directed microtubule motor proteins, kinesin-1 and dynein, localize to the nuclear envelope in myotubes. Kinesin-1 localization is mediated at least in part by interaction with klarsicht/ANC-1/Syne homology (KASH) proteins. Depletion of kinesin-1 abolishes nuclear rotation and significantly inhibits nuclear translocation, resulting in the abnormal aggregation of nuclei at the midline of the myotube. Dynein depletion also inhibits nuclear dynamics, but to a lesser extent, leading to altered spacing between adjacent nuclei. Thus, oppositely directed motors acting from the surface of the nucleus drive nuclear motility in myotubes. The variable dynamics observed for individual nuclei within a single myotube likely result from the stochastic activity of competing motors interacting with a complex bipolar microtubule cytoskeleton that is also continuously remodeled as the nuclei move. The three-dimensional rotation of myotube nuclei may facilitate their motility through the complex and crowded cellular environment of the developing muscle cell, allowing for proper myonuclear positioning.

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Inhibiting myostatin reverses muscle fibrosis through apoptosis

Advance Online Publication June 8, 2012 doi: 10.1242/?jcs.090365 Zhao Bo Li, Jiangyang Zhang and Kathryn R. Wagner*?*Communicating Author: Kathryn R. Wagner, M.D., Ph.D., Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, The Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, MD 21205, 443-923-9525 (t), 443-923-9545 (f), wagnerk{at}kennedykrieger.orgSkeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibiting myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc), reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existed muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.

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