Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies

Pecorari, Ilaria; Mestroni, Luisa; Sbaizero, Orfeo

doi:10.3390/ijms21165865

Cited by 9 publications

(6 citation statements)

References 71 publications

(155 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elevated levels in females may be explained by its gene location on the X-chromosome. Mutations in DMD have been associated with muscular dystrophies and X-linked dilated cardiomyopathy ( 42 ). LMOD2 is the cardiac isoform of leiomodin, an actin-binding protein involved in thin filament assembly.…”

Section: Discussionmentioning

confidence: 99%

Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy

Schuldt

Dorsch

Knol

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Background: Sex-differences in clinical presentation contribute to the phenotypic heterogeneity of hypertrophic cardiomyopathy (HCM) patients. While disease prevalence is higher in men, women present with more severe diastolic dysfunction and worse survival. Until today, little is known about the cellular differences underlying sex-differences in clinical presentation.Methods: To define sex-differences at the protein level, we performed a proteomic analysis in cardiac tissue obtained during myectomy surgery to relieve left ventricular outflow tract obstruction of age-matched female and male HCM patients harboring a sarcomere mutation (n = 13 in both groups). Furthermore, these samples were compared to 8 non-failing controls. Women presented with more severe diastolic dysfunction.Results: Out of 2099 quantified proteins, direct comparison of male, and female HCM samples revealed only 46 significantly differentially expressed proteins. Increased levels of tubulin and heat shock proteins were observed in female compared to male HCM patients. Western blot analyses confirmed higher levels of tubulin in female HCM samples. In addition, proteins involved in carbohydrate metabolism were significantly lower in female compared to male samples. Furthermore, we found lower levels of translational proteins specifically in male HCM samples. The disease-specificity of these changes were confirmed by a second analysis in which we compared female and male samples separately to non-failing control samples. Transcription factor analysis showed that sex hormone-dependent transcription factors may contribute to differential protein expression, but do not explain the majority of protein changes observed between male and female HCM samples.Conclusion: In conclusion, based on our proteomics analyses we propose that increased levels of tubulin partly underlie more severe diastolic dysfunction in women compared to men. Since heat shock proteins have cardioprotective effects, elevated levels of heat shock proteins in females may contribute to later disease onset in woman, while reduced protein turnover in men may lead to the accumulation of damaged proteins which in turn affects proper cellular function.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy

Schuldt

Dorsch

Knol

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…The multi-protein Z-disc complex is crucial for lateral and longitudinal force transmission [ 6 ] and simultaneously acts as a signaling hub to regulate cellular functions [ 7 , 8 ]. Hence, it has become evident, that knowledge of the fundamental cytoarchitecture and mechanical properties of CMs are prerequisites to explain the causes and consequences of cardiomyopathies [ 9 ]. Only a complete understanding of the contractile apparatus and the events occurring at the sarcomere level will improve our knowledge of the whole heart in healthy and diseased conditions.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of laser induced sarcomere micro-damage: Role of damage extent and location in cardiomyocytes

et al. 2021

View full text Add to dashboard Cite

Whereas it is evident that a well aligned and regular sarcomeric structure in cardiomyocytes is vital for heart function, considerably less is known about the contribution of individual elements to the mechanics of the entire cell. For instance, it is unclear whether altered Z-disc elements are the reason or the outcome of related cardiomyopathies. Therefore, it is crucial to gain more insight into this cellular organization. This study utilizes femtosecond laser-based nanosurgery to better understand sarcomeres and their repair upon damage. We investigated the influence of the extent and the location of the Z-disc damage. A single, three, five or ten Z-disc ablations were performed in neonatal rat cardiomyocytes. We employed image-based analysis using a self-written software together with different already published algorithms. We observed that cardiomyocyte survival associated with the damage extent, but not with the cell area or the total number of Z-discs per cell. The cell survival is independent of the damage position and can be compensated. However, the sarcomere alignment/orientation is changing over time after ablation. The contraction time is also independent of the extent of damage for the tested parameters. Additionally, we observed shortening rates between 6–7% of the initial sarcomere length in laser treated cardiomyocytes. This rate is an important indicator for force generation in myocytes. In conclusion, femtosecond laser-based nanosurgery together with image-based sarcomere tracking is a powerful tool to better understand the Z-disc complex and its force propagation function and role in cellular mechanisms.

show abstract

“…Mutations in genes encoding these proteins are associated with human cardiomyopathies, which are the leading cause of death worldwide. 3–8 One important component among these proteins is FLNC (filamin C), a member of the FLN (filamin) protein family.…”

mentioning

confidence: 99%

Interaction of Filamin C With Actin Is Essential for Cardiac Development and Function

Zhou

Fang

Ithychanda

et al. 2023

Circulation Research

View full text Add to dashboard Cite

Background: FLNC (filamin C), a member of the FLN family predominantly expressed in striated muscles, plays a crucial role in bridging the cytoskeleton and ECM (extracellular matrix) in cardiomyocytes, thereby maintaining heart integrity and function. Although genetic variants within the N-terminal ABD (actin-binding domain) of FLNC have been identified in patients with cardiomyopathy, the precise contribution of the actin-binding capability to FLNC’s function in mammalian hearts remains poorly understood. Methods: We conducted in silico analysis of the 3-dimensional structure of mouse FLNC to identify key amino acid residues within the ABD that are essential for FLNC’s actin-binding capacity. Subsequently, we performed coimmunoprecipitation and immunofluorescent assays to validate the in silico findings and assess the impact of these mutations on the interactions with other binding partners and the subcellular localization of FLNC. Additionally, we generated and analyzed knock-in mouse models in which the FLNC-actin interaction was completely disrupted by these mutations. Results: Our findings revealed that F93A/L98E mutations completely disrupted FLNC-actin interaction while preserving FLNC’s ability to interact with other binding partners ITGB1 (β1 integrin) and γ-SAG (γ-sarcoglycan), as well as maintaining FLNC subcellular localization. Loss of FLNC-actin interaction in embryonic cardiomyocytes resulted in embryonic lethality and cardiac developmental defects, including ventricular wall malformation and reduced cardiomyocyte proliferation. Moreover, disruption of FLNC-actin interaction in adult cardiomyocytes led to severe dilated cardiomyopathy, enhanced lethality and dysregulation of key cytoskeleton components. Conclusions: Our data strongly support the crucial role of FLNC as a bridge between actin filaments and ECM through its interactions with actin, ITGB1, γ-SAG, and other associated proteins in cardiomyocytes. Disruption of FLN-actin interaction may result in detachment of actin filaments from the extracellular matrix, ultimately impairing normal cardiac development and function. These findings also provide insights into mechanisms underlying cardiomyopathy associated with genetic variants in FLNC ABD and other regions.

show abstract

Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies

Cited by 9 publications

References 71 publications

Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy

Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy

Evaluation of laser induced sarcomere micro-damage: Role of damage extent and location in cardiomyocytes

Interaction of Filamin C With Actin Is Essential for Cardiac Development and Function

Contact Info

Product

Resources

About