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Published on: November 29, 2011
Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes
Matthew J Brody1, Davy Vanhoutte1, Tobias G Schips1
1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Insights
Thrombospondin-4 (Thbs4) protects muscle by acting inside cells. However, secretion is crucial for Thbs4 to stabilize muscle membranes and prevent damage, as shown in mouse models of heart and muscle disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Thrombospondins (Thbs) are secreted proteins involved in tissue repair.
- Thrombospondin-4 (Thbs4) protects cardiac and skeletal muscle by activating endoplasmic reticulum (ER) stress responses and enhancing membrane stability.
- The precise location of Thbs4 action (intracellular, extracellular, or secretion-dependent) for these protective effects remains unclear.
Purpose of the Study:
- To investigate the intracellular and secretion-dependent functions of Thbs4 in muscle.
- To determine if Thbs4 requires secretion to exert its protective effects on sarcolemmal stability.
- To elucidate the role of Thbs4 in models of cardiac and muscular dystrophy.
Main Methods:
- Generation of transgenic mice with cardiac cell-specific overexpression of a secretion-defective Thbs4 mutant.
- Evaluation of ER stress response, ER expansion, and sarcolemmal integrity in cardiomyocytes.
- Assessment of Thbs4 function in the mdx mouse model of Duchenne muscular dystrophy.
- Expression of wild-type and secretion-defective Thbs4 in Drosophila to study muscle function.
Main Results:
- Secretion-defective Thbs4 upregulated ER stress and expanded ER/vesicles intracellularly, similar to wild-type Thbs4.
- Only secretion-defective Thbs4 induced cardiomyopathy with sarcolemmal rupture, linked to reduced membrane glycoproteins.
- Thbs4 deletion in mdx mice exacerbated cardiomyocyte membrane instability and cardiomyopathy.
- Overexpression of secretion-defective Thbs4 in Drosophila impaired muscle function and sarcomere alignment, unlike wild-type Thbs4.
Conclusions:
- Transit through the secretory pathway is essential for Thbs4 to enhance sarcolemmal stability.
- ER stress induction and ER/vesicular expansion by Thbs4 are intracellular processes.
- Thbs4's protective role in muscle membrane integrity is secretion-dependent, while its effects on ER stress are intracellular.
Abstract:
Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle, where it activates an adaptive endoplasmic reticulum (ER) stress response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. In this study, we generated transgenic mice with cardiac cell-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of Thbs4 in the mdx mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in Drosophila, but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 are exclusively intracellular processes.
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