Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
| Autor: | Jineet Patel, Lori L. Wallrath, Ashley J. Earle, Sushruta Iruvanti, Gisèle Bonne, Philipp Isermann, Steven A. Moore, Jan Lammerding, Tyler J. Kirby, Gregory R. Fedorchak |
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| Přispěvatelé: | AMS - Tissue Function & Regeneration, ACS - Heart failure & arrhythmias, Physiology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities DNA damage 02 engineering and technology Biology 010402 general chemistry medicine.disease_cause 01 natural sciences LMNA 03 medical and health sciences 0302 clinical medicine medicine Myocyte General Materials Science Muscular dystrophy Cytoskeleton 030304 developmental biology 0303 health sciences Mutation integumentary system Mechanical Engineering Skeletal muscle General Chemistry 021001 nanoscience & nanotechnology Condensed Matter Physics medicine.disease Chromatin 0104 chemical sciences Cell biology medicine.anatomical_structure Mechanics of Materials Congenital muscular dystrophy 0210 nano-technology 030217 neurology & neurosurgery Lamin |
| Zdroj: | Earle*, A J, Kirby*, T J, Fedorchak*, G R, Isermann, P, Patel, J, Iruvanti, S, Moore, S A, Bonne, G, Wallrath, L L & Lammerding, J 2020, ' Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells ', Nat. Mater., vol. 19, no. 4, pp. 464-473 . https://doi.org/10.1038/s41563-019-0563-5 Nat. Mater., 19(4), 464-473. Nature Publishing Group |
| ISSN: | 1476-1122 |
| DOI: | 10.1038/s41563-019-0563-5 |
| Popis: | Mutations in the humanLMNAgene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found thatLmnamutations caused extensive NE abnormalities, consisting of chromatin protrusions into the cytoplasm and transient rupture of the NE in skeletal muscle cells. NE damage was associated with DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, NE damage resulted from nuclear migration in maturing skeletal muscle cells, rather than actomyosin contractility. NE damage and DNA damage was reduced by either depletion of kinesin-1 or disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. LINC complex disruption rescued myofiber function and viability inLmnamutant myofibers, indicating that the myofiber dysfunction is the result of mechanically induced NE damage. The extent of NE damage and DNA damage inLmnamouse models correlated with the disease onset and severityin vivo. Moreover, inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients withLMNAmuscular dystrophy revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor forLMNAskeletal muscle diseases. |
| Databáze: | OpenAIRE |
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