Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA...

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Genetics

Background:

• Mutations in the LMNA gene cause laminopathies, frequently affecting the heart.
• The precise mechanisms driving LMNA-associated cardiac dysfunction are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular pathogenesis of LMNA-related cardiomyopathy.
• To identify therapeutic targets for LMNA-associated heart disease.

Main Methods:

• Conditional cardiomyocyte-specific Lmna deletion in adult mice.
• Translatome profiling to analyze gene expression changes.
• Assessment of nuclear, Golgi, and autophagy integrity.
• Evaluation of therapeutic interventions targeting stress pathways.

Main Results:

• Mice with cardiomyocyte-specific Lmna deletion rapidly developed cardiomyopathy and pathological remodeling.
• Nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress were observed prior to cardiac dysfunction.
• Translatome profiling revealed MED25 activation, linked to Golgi stress.
• Autophagy disruption was evident and could be mimicked by Golgi disruption.
• Modulators of autophagy or ER stress administration delayed cardiac dysfunction and improved survival.

Conclusions:

• Stress responses originating from the perinuclear space, involving Golgi and autophagy, are critical in LMNA cardiomyopathy pathogenesis.
• Targeting autophagy and ER stress pathways shows therapeutic potential for LMNA-related heart conditions.