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Lem2 is essential for cardiac development by maintaining nuclear integrity.

Jacob A Ross1, Nathaly Arcos-Villacis1, Edmund Battey1,2

  • 1British Heart Foundation Centre of Research Excellence, School of Cardiovascular & Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK.

Cardiovascular Research
|April 17, 2023
PubMed
Summary

Lem2 is crucial for embryonic heart development, protecting the nucleus from contraction forces. Adult hearts tolerate partial Lem2 loss, suggesting developmental roles are more critical.

Keywords:
Cardiac developmentHeart failureLINC complexLaminopathyNuclear Envelope

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Area of Science:

  • Cardiovascular Biology
  • Nuclear Envelope Biology
  • Genetic Disease Mechanisms

Background:

  • Nuclear envelope (NE) integrity is vital for cellular function.
  • Mutations in NE proteins are a significant cause of familial dilated cardiomyopathy.
  • Lem2, a NE protein, is implicated in human cardiomyopathy and mouse heart development, but its cardiac role is unclear.

Purpose of the Study:

  • To investigate the role of Lem2 in embryonic and adult cardiomyocyte function and cardiac development.
  • To elucidate the mechanisms by which Lem2 deficiency impacts heart integrity.
  • To understand the implications for human cardiomyopathies.

Main Methods:

  • Generation of embryonic (Lem2 cKO) and adult (Lem2 iCKO) cardiomyocyte-specific Lem2 knockout mouse models.
  • High-resolution episcopic microscopy for 3D morphological analysis.
  • RNA-sequencing, immunofluorescence, isolated cardiomyocyte studies, and echocardiography.

Main Results:

  • Lem2 ablation in embryonic cardiomyocytes caused underdeveloped hearts with DNA damage, nuclear rupture, and apoptosis.
  • These embryonic defects were exacerbated by muscle contraction and ameliorated by inhibiting myosin and calcium channels.
  • Partial Lem2 depletion in adult cardiomyocytes did not cause overt cardiac dysfunction up to 18 months.

Conclusions:

  • Lem2 is essential for maintaining nuclear envelope integrity in developing hearts, protecting against mechanical stress from muscle contraction.
  • The adult heart exhibits resilience to partial Lem2 depletion, possibly due to NE maturation and stress adaptation.
  • Findings offer insights into Lem2-associated cardiomyopathy and cardio-laminopathies.