Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Ashley J Earle; Tyler J Kirby; Gregory R Fedorchak; Philipp Isermann; Jineet Patel; Sushruta Iruvanti; Steven A Moore; Gisèle Bonne; Lori L Wallrath; Jan Lammerding

doi:10.1038/s41563-019-0563-5

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Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Journal article

Peer reviewed

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Ashley J Earle, Tyler J Kirby, Gregory R Fedorchak, Philipp Isermann, Jineet Patel, Sushruta Iruvanti, Steven A Moore, Gisèle Bonne, Lori L Wallrath and Jan Lammerding

Nature materials, Vol.19(4), pp.464-473

04/2020

DOI: 10.1038/s41563-019-0563-5

PMCID: PMC7102937

PMID: 31844279

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https://pure.amsterdamumc.nl/en/publications/6324a244-c582-4183-b41f-b4bb200cf8f2View

Open Access

Abstract

Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy and other diseases collectively known as laminopathies. The mechanisms responsible for these diseases remain incompletely understood. Using three mouse models of muscle laminopathies and muscle biopsies from individuals with LMNA-related muscular dystrophy, we found that Lmna mutations reduced nuclear stability and caused transient rupture of the NE in skeletal muscle cells, resulting in DNA damage, DNA damage response activation and reduced cell viability. NE and DNA damage resulted from nuclear migration during skeletal muscle maturation and correlated with disease severity in the mouse models. Reduction of cytoskeletal forces on the myonuclei prevented NE damage and rescued myofibre function and viability in Lmna mutant myofibres, indicating that myofibre dysfunction is the result of mechanically induced NE damage. Taken together, these findings implicate mechanically induced DNA damage as a pathogenic contributor to LMNA skeletal muscle diseases.

Animals

DNA Damage

Lamin Type A - genetics

Lamin Type A - metabolism

Mice

Mice, Knockout

Muscular Dystrophy, Animal - genetics

Muscular Dystrophy, Animal - metabolism

Muscular Dystrophy, Animal - pathology

Mutation

Myofibrils - metabolism

Myofibrils - pathology

Nuclear Envelope - genetics

Nuclear Envelope - metabolism

Nuclear Envelope - pathology

Details

Title: Subtitle: Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
Creators: Ashley J Earle - Cornell University
Tyler J Kirby - Cornell University
Gregory R Fedorchak - Cornell University
Philipp Isermann - Cornell University
Jineet Patel - Cornell University
Sushruta Iruvanti - Cornell University
Steven A Moore - University of Iowa
Gisèle Bonne - Université Paris Cité
Lori L Wallrath - University of Iowa
Jan Lammerding - Cornell University
Resource Type: Journal article
Publication Details: Nature materials, Vol.19(4), pp.464-473
DOI: 10.1038/s41563-019-0563-5
PMID: 31844279
PMCID: PMC7102937
NLM abbreviation: Nat Mater
ISSN: 1476-1122
eISSN: 1476-4660
Grant note: U54 CA210184 / NCI NIH HHS U54 NS053672 / NINDS NIH HHS R01 HL082792 / NHLBI NIH HHS
Language: English
Date published: 04/2020
Academic Unit: Pathology; Biochemistry and Molecular Biology; University College Courses
Record Identifier: 9984186517802771

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