Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Mechanisms of Disease

Background:

• Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people, with unclear molecular causes despite identified gene mutations.
• Current genetic markers for HCM do not reliably predict disease onset or patient outcomes.
• The precise molecular mechanisms driving HCM pathogenesis remain largely unknown.

Purpose of the Study:

• To investigate the role of vacuolar protein sorting 34 (Vps34) in the development of hypertrophic cardiomyopathy (HCM).
• To explore the Vps34-αB-crystallin (CryAB) interaction in cardiac pathology.
• To identify novel molecular pathways implicated in HCM etiology.

Main Methods:

• Assessed cardiac Vps34 expression in a subset of HCM patients.
• Utilized a muscle-specific Vps34 knockout mouse model to study HCM development.
• Analyzed cardiac histopathology, protein aggregation (CryAB), and proteolysis pathways (ESCRT-mediated degradation).

Main Results:

• Reduced cardiac Vps34 expression was observed in a subset of HCM patients.
• Muscle-specific Vps34 deficiency in mice induced HCM-like symptoms and sudden cardiac death.
• Vps34-deficient hearts showed myofibrillar disarray and CryAB aggregates due to impaired proteolysis.
• CryAB deposition correlated with decreased Vps34 levels in HCM patient myocardial samples.

Conclusions:

• Cardiac Vps34 deficiency is linked to HCM pathogenesis.
• The Vps34-CryAB axis, involving ESCRT-mediated proteolysis, is crucial for maintaining cardiac homeostasis.
• Disruption of the Vps34-CryAB pathway represents a potential novel etiology for hypertrophic cardiomyopathy.