# Nuclear mechanics and mechanotransduction in muscular laminopathies

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $493,927

## Abstract

Project Summary
The long-term goal of this project is to determine how mutations in the human LMNA gene encoding the nuclear
envelope (NE) proteins lamin A and C cause severe cardiac and skeletal muscle diseases. This research is
important because mutations in the LMNA gene are responsible for approximately 10% of all genetically inherited
cases of dilated cardiomyopathy, and LMNA-associated cardiomyopathies have a particularly poor prognosis.
Individuals with LMNA-associated muscular dystrophy suffer from debilitating progressive muscle wasting and
die from dilated cardiomyopathy. To date, no effective treatments are available for the cardiac and skeletal
muscle defects caused by LMNA mutations, and it remains unclear how LMNA mutations result in muscle-
specific defects. The incomplete understanding of the disease pathogenesis presents a major hurdle in the
development of effective treatments. Building on recently published and extensive preliminary data, this project
proposes a novel hypothesis for the pathogenesis of laminopathies affecting cardiac and skeletal muscle: LMNA
mutations associated with striated muscle disease reduce nuclear mechanical stability. In skeletal and cardiac
tissues, the fragile nuclei are then prone to mechanically induced damage to the NE (‘NE rupture’) due to
cytoskeletal forces acting on myonuclei during muscle cell contraction and maturation. The NE rupture results in
DNA damage and activation of DNA damage response pathways, which lead to cell death, senescence, and
metabolic impairment responsible for the progressive cardiac and skeletal muscle defects. Additional
mechanisms, such as disturbed transcriptional regulation and increased production of reactive oxygen species,
may further contribute to the increased DNA damage and activation of DNA damage response pathways in the
LMNA mutant muscle cells. The proposed work takes advantage of several in vitro and in vivo models and
assays that were custom-developed in the PI’s laboratory to measure nuclear mechanics and mechanically
induced damage in living cells and fixed tissues. The proposed project aims to: (1) determine the molecular and
biophysical mechanisms that cause the increased NE rupture, DNA damage, and DNA damage response
activation in skeletal and cardiac muscle cells in laminopathies; (2) identify the molecular pathways leading from
NE rupture, DNA damage, and DNA damage response activation to striated muscle cell death and dysfunction;
and (3) evaluate if inhibiting hyperactive DNA damage response pathways or reducing physical stress on the
nucleus improves cardiac and skeletal muscle health in mouse models of LMNA-associated disease. The
proposed studies will establish the functional role of nuclear damage observed in laminopathies and provide new
insights into the pathogenesis of laminopathies affecting cardiac and skeletal muscle, with the potential to
discover novel therapeutic targets and strategies that could significantly enhance the treatmen...

## Key facts

- **NIH application ID:** 10071633
- **Project number:** 2R01HL082792-11A1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Jan Lammerding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,927
- **Award type:** 2
- **Project period:** 2007-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071633

## Citation

> US National Institutes of Health, RePORTER application 10071633, Nuclear mechanics and mechanotransduction in muscular laminopathies (2R01HL082792-11A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071633. Licensed CC0.

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