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Sorbs2 Deficiency Causes Diastolic Dysfunction Through Dysregulation of Cytoskeletal Networks and Calcium Handling

ABSTRACT: Sorbin and SH3 domain–containing protein 2 (Sorbs2) is a cytoskeletal adaptor protein implicated in cardiomyocyte adhesion, cytoskeletal remodeling, and calcium handling. We investigated its role in diastolic dysfunction using Sorbs2 knockout (KO) mice. Sorbs2 KO mice developed progressive diastolic dysfunction with preserved systolic function, accompanied by left atrial enlargement, pulmonary edema, myocardial fibrosis, increased microtubule detyrosination, and impaired calcium handling. Bulk RNA-seq was performed on ventricular myocardium from wild-type (WT) and KO mice at 6 weeks and 6 months of age, with additional rescue experiments using AAV9-mediated re-expression of Sorbs2. RNA-seq revealed activation of extracellular matrix pathways and integrin signaling in KO mice, while mitochondrial metabolic pathways were downregulated. These data establish Sorbs2 as a critical regulator of diastolic function.

ORGANISM(S): Mus musculus

PROVIDER: GSE306787 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Rationale Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and is associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with findings that microtubule detyrosination (dTyr-MTs) is markedly elevated in heart failure. Acute reduction of dTyr-MTs by inhibition of the detyrosinase (VASH/SVBP complex) or activation of the tyrosinase (tubulin tyrosine ligase, TTL) markedly improved contractility and reduced stiffness in human failing cardiomyocytes, presenting a new perspective for HCM treatment. Objective In this study, we tested the impact of chronic tubulin tyrosination in a HCM mouse model (Mybpc3-knock-in; KI), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). Methods and Results AAV9-mediated TTL transfer was applied in neonatal wild-type (WT) rodents, in 3-week-old KI mice, and in HCM human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We show: i) TTL for 6 weeks dose-dependently reduced dTyr-MTs and improved contractility without affecting cytosolic calcium transients in WT cardiomyocytes. ii) TTL for 12 weeks reduced the abundance of dTyr-MTs in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in KI mice. iii) TTL for 10 days normalized cell area in HCM hiPSC-cardiomyocytes. iv) TTL overexpression activates transcription of several tubulin isoforms, and omics GO analysis revealed enrichment of components of the cytoskeleton, sarcomere Z-disc, mitochondria, and intercalated disc in KI mice. v) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and WT EHTs. RNA-seq and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-KO vs. TTL-KO EHTs. Conclusion This study provides the first proof-of-concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the non-sarcomeric cytoskeleton in heart disease.

Project description:BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME. METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we established an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt−/−) Nnt in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6–10). RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e′) ratio (E/e′) (42.8 versus 21.5, P=1.2×10−10), E/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4, P=4.1×10−2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10−3), and myocardial fibrosis (P=2.3×10−2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10−3) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG, P=2.6×10−2) among Nnt+/+ mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in myocardial fibrosis. CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.

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Sorbs2 Deficiency Causes Diastolic Dysfunction Through Dysregulation of Cytoskeletal Networks and Calcium Handling

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