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Modeling Myotonic Dystrophy 1 in C2C12 Myoblast Cells
Published on: July 29, 2016
Biomechanical characterization of a desminopathy in primary human myoblasts
Navid Bonakdar1, Justyna Luczak, Lena Lautscham
1Department of Physics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Abstract:
Heterozygous mutations of the human desmin gene on chromosome 2q35 cause hereditary and sporadic myopathies and cardiomyopathies. The expression of mutant desmin brings about partial disruption of the extra sarcomeric desmin cytoskeleton and abnormal protein aggregation in the sarcoplasm of striated muscle cells. The precise molecular pathways and sequential steps that lead from a desmin gene defect to progressive muscle damage are still unclear. We tested whether mutant desmin changes the biomechanical properties and the intrinsic mechanical stress response of primary cultured myoblasts derived from a patient carrying a heterozygous R350P desmin mutation. Compared to wildtype controls, undifferentiated mutant desmin myoblasts revealed increased cell death and substrate detachment in response to cyclic stretch on flexible membranes. Moreover, magnetic tweezer microrheometry of myoblasts using fibronectin-coated beads showed increased stiffness of diseased cells. Our findings provide the first evidence that altered mechanical properties may contribute to the progressive striated muscle pathology in desminopathies. We postulate that the expression of mutant desmin leads to increased mechanical stiffness, which results in excessive mechanical stress in response to strain and consecutively to increased mechanical vulnerability and damage of muscle cells.
Insights
Mutant desmin in muscle cells increases stiffness, leading to cell damage and death. This finding suggests altered mechanical properties contribute to desmin-related muscle diseases.
Area of Science:
- Muscle Biology
- Cellular Biomechanics
- Genetics of Muscle Disorders
Background:
- Desminopathies are muscle disorders caused by mutations in the desmin gene (DES).
- Mutant desmin disrupts the muscle cytoskeleton and forms aggregates, but the link to muscle damage is unclear.
- Understanding the mechanical consequences of mutant desmin is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the impact of a specific heterozygous R350P desmin mutation on the biomechanical properties of primary myoblasts.
- To determine if mutant desmin alters the intrinsic mechanical stress response of muscle cells.
Main Methods:
- Primary myoblasts from a patient with a heterozygous R350P desmin mutation were cultured.
- Myoblasts were subjected to cyclic stretch on flexible membranes to assess cell death and substrate detachment.
- Magnetic tweezer microrheometry was used to measure the stiffness of myoblasts coated with fibronectin beads.
Main Results:
- Mutant desmin myoblasts exhibited increased cell death and substrate detachment under cyclic stretch compared to wildtype controls.
- Magnetic tweezer experiments revealed significantly increased stiffness in myoblasts expressing mutant desmin.
- These findings indicate altered cellular biomechanics in the presence of mutant desmin.
Conclusions:
- The study provides the first evidence that altered mechanical properties of muscle cells contribute to the pathology of desminopathies.
- Increased mechanical stiffness due to mutant desmin expression may lead to excessive stress and vulnerability, resulting in muscle cell damage.
- These findings highlight the role of cellular biomechanics in the progression of desmin-related muscle diseases.
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