Two defining characteristics of muscle cells are the many precisely positioned nuclei and the linearly arranged sarcomeres, yet the relationship between these two features is not known. We show that nuclear positioning precedes sarcomere formation. Furthermore, ZASP-GFP, a Z-line protein, colocalizes with F-actin in puncta at the cytoplasmic face of nuclei before sarcomere assembly. In embryos with mispositioned nuclei, ZASP-GFP is still recruited to the nuclei before its incorporation into sarcomeres. Furthermore, the first sarcomeres appear in positions close to the nuclei, regardless of nuclear position. These data suggest that the interaction between sarcomere proteins and nuclei is not dependent on properly positioned nuclei. Mechanistically, ZASP-GFP localization to the cytoplasmic face of the nucleus did require the linker of nucleoskeleton and cytoskeleton (LINC) complex. Muscle-specific depletion of klarsicht (nesprin) or klariod (SUN) blocked the recruitment of ZASP-GFP to the nucleus during the early stages of sarcomere assembly. As a result, sarcomeres were poorly formed and the general myofibril network was less stable, incomplete, and/or torn. These data suggest that the nucleus, through the LINC complex, is crucial for the proper assembly and stability of the sarcomere network.
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http://dx.doi.org/10.1091/mbc.E16-01-0021 | DOI Listing |
Am J Med Genet A
January 2025
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Hypertrophic cardiomyopathy (HCM) is rare in childhood, but it is associated with significant morbidity and mortality. Genetic causes of HCM are mostly related to sarcomeric genes abnormalities; however, syndromic, metabolic, and mitochondrial disorders play an important role in its etiopathogenesis in pediatric patients. We here describe a new case of apparently isolated HCM due to mitochondrial assembly factor gene NDUFAF1 biallelic variants (c.
View Article and Find Full Text PDFFASEB J
January 2025
Department of Biochemistry and Molecular Biology, Institute of Marine and Environmental Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Clin Genet
January 2025
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder associated with 1/3000 to 1/5000 live births. We report a consanguineous family with multiple affected members with AMC and identified a recessive mutation in the highly conserved splice donor site, resulting in the mis-splicing of the affected exons. SENP7 is a deSUMOylase that is critical for sarcomere assembly and skeletal muscle contraction by regulating the transcriptional program in the skeletal muscle.
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December 2024
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Neddylation is a highly conserved post-translational modification that plays critical roles in various cellular processes through the modulation of cullins and non-cullin substrates. While neddylation is known to be essential for embryonic development, tumor growth, and organogenesis of different tissues, its role in cardiogenesis remains unexplored. Here, we investigated the role of neddylation in early cardiac development by deleting the gene encoding a regulatory subunit of the NEDD8-specific E1 activating enzyme, Nae1, globally and in a heart-specific fashion via Nkx2-5.
View Article and Find Full Text PDFElife
December 2024
Translational Cardiology and Functional Genomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
The giant striated muscle protein titin integrates into the developing sarcomere to form a stable myofilament system that is extended as myocytes fuse. The logistics underlying myofilament assembly and disassembly have started to emerge with the possibility to follow labeled sarcomere components. Here, we generated the mCherry knock-in at titin's Z-disk to study skeletal muscle development and remodeling.
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