SORBS2 regulates diastolic function through cytoskeletal networks and calcium handling

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Diastolic dysfunction is key in heart failure with preserved ejection fraction.
• Mechanisms within cardiomyocytes are not fully understood.
• SORBS2's role in cardiac function is unclear.

Purpose of the Study:

• Investigate the role of SORBS2 in cardiomyocyte adhesion complexes.
• Determine the impact of SORBS2 deficiency on cardiac function and survival.
• Elucidate the molecular mechanisms by which SORBS2 regulates diastolic function.

Main Methods:

• Genetic ablation of SORBS2 in mice.
• Assessment of cardiac structure and function (diastolic and systolic indices).
• Analysis of cardiomyocyte adhesion complexes, cytoskeletal remodeling, calcium homeostasis, and extracellular matrix remodeling.

Main Results:

• SORBS2 genetic ablation led to progressive diastolic dysfunction, atrial enlargement, and reduced survival in mice.
• Postnatal re-expression of SORBS2 rescued diastolic function and improved longevity.
• SORBS2 deficiency disrupted microtubule organization, reduced SERCA2, impaired calcium handling, and promoted fibrosis.
• Pharmacological inhibition of microtubule detyrosination partially rescued relaxation defects.

Conclusions:

• SORBS2 is essential for cardiomyocyte adhesion and regulating diastolic function.
• SORBS2 acts as a scaffold linking cytoskeletal integrity, calcium homeostasis, and extracellular matrix.
• Targeting SORBS2 or associated pathways may offer therapeutic strategies for diastolic dysfunction.