What is the clinical evidence from this study?

Study design: Other. Population: Diastolic dysfunction. Intervention: AAV9-Tnnt2-SORBS2 vs. Untreated Sorbs2 knockout mice. Primary outcome: Diastolic function and survival.

What question did this study set out to answer?

The study aims to elucidate the role of SORBS2 in diastolic function and its underlying mechanisms in cardiomyocytes.

June 18, 2026Communications Biology0 citationsOpen Access

SORBS2 regulates diastolic function through cytoskeletal networks and calcium handling

ZWZexuan WuBoston Children's Hospital CBCamille BlandinBoston Children's Hospital JCJiehui ChenSouth China Normal University

Key Result

Genetic ablation of SORBS2 in mice caused progressive diastolic dysfunction with preserved systolic function, which was rescued by postnatal cardiomyocyte-directed AAV-mediated re-expression of SORBS2.

Key Points

The study aims to elucidate the role of SORBS2 in diastolic function and its underlying mechanisms in cardiomyocytes.
Genetic ablation of SORBS2 in murine models to assess its impact on diastolic function.
Postnatal cardiomyocyte-directed re-expression of SORBS2 to evaluate improvements in diastolic indices.
Pharmacological inhibition of microtubule detyrosination to examine restoration of relaxation defects.
SORBS2 deficiency caused progressive diastolic dysfunction with preserved systolic function and led to atrial enlargement.
Postnatal re-expression of SORBS2 significantly improved diastolic indices and increased survival rates.
Inhibition of microtubule detyrosination partially rescued relaxation defects, indicating its role in cardiac function.

Structured PICO

Does SORBS2 regulate diastolic function and myocardial mechanics in a murine model?

Population

Murine model of Sorbs2 knockout to study diastolic dysfunction and AAV-mediated gene therapy rescue.

Intervention

Genetic ablation of SORBS2, postnatal cardiomyocyte-directed re-expression of SORBS2, and pharmacological inhibition of microtubule detyrosination

Comparator

Control/wild-type mice (implied)

Outcome

Diastolic function, ventricular stiffness, and survivalsurrogate

SORBS2 is identified as a critical regulator of diastolic function and myocardial mechanics, providing a potential therapeutic target for heart failure with preserved ejection fraction.

Limitations

Global Sorbs2 knockout model used, limiting conclusions about cell-autonomous function.
Late death of AAV-treated mice might be due to insufficient expression or requirement in other cell types.
Direct atrial cardiomyocyte role cannot be fully excluded.
Further studies required to elucidate contribution to human heart disease.

Abstract

Abstract Diastolic dysfunction, defined by impaired relaxation and increased ventricular stiffness, is central to heart failure with preserved ejection fraction, yet cardiomyocyte-intrinsic mechanisms remain incompletely understood. Here, we show that SORBS2 is a vital component of murine cardiomyocyte adhesion complexes. Its genetic ablation in mice causes progressive diastolic dysfunction with preserved systolic function, accompanied by atrial enlargement and reduced survival. Postnatal cardiomyocyte-directed re-expression of SORBS2 restores diastolic indices and significantly improves longevity. Mechanistically, SORBS2 functions as an integrative scaffold linking adhesome integrity, cytoskeletal remodeling, and calcium homeostasis. SORBS2 deficiency increases microtubule detyrosination, reduces SERCA2 abundance, disrupts dyad-associated organization, which collectively impair active cardiomyocyte relaxation. Concurrently, this deficiency promotes extracellular matrix remodeling and myocardial fibrosis, driving passive ventricular stiffness. Pharmacological inhibition of microtubule detyrosination partially rescues relaxation defects. These findings establish SORBS2 as a key regulator of diastolic function and define a structural axis governing myocardial mechanics, offering potential therapeutic targets.

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