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Updated: Jul 4, 2026
Single Myofiber Isolation and Culture from a Murine Model of Emery-Dreifuss Muscular Dystrophy in Early Post-Natal Development
Published on: July 1, 2020
Mice expressing L345P mutant desmin exhibit morphological and functional changes of skeletal and cardiac mitochondria
Anna Kostareva1, Gunnar Sjöberg, Joseph Bruton
1Department of Woman and Child Health and Center for Molecular Medicine, Karolinska Institute, L8:02, Stockholm 17176, Sweden.
Abstract:
Desmin mutations underlie inherited myopathies/cardiomyopathies with varying severity and involvement of the skeletal and cardiac muscles. We developed a transgenic mouse model expressing low level of the L345P desmin mutation (DESMUT mice) in order to uncover changes in skeletal and cardiac muscles caused by this mutation. The most striking ultrastructural changes in muscle from DESMUT mice were mitochondrial swelling and vacuolization. The mitochondrial Ca(2+) level was significantly increased in skeletal and cardiac myocytes from DESMUT mice compared to wild type cells during and after contractions. In isolated DESMUT soleus muscles, contractile function and recovery from fatigue were impaired. A SHIRPA screening test for neuromuscular performance demonstrated decreased motor function in DESMUT compared to WT mice. Echocardiographic changes in DESMUT mice included left ventricular wall hypertrophy and a decreased left ventricular chamber dimension. The results imply that low levels of L345P desmin acts, at least partially, by a dominant negative effect on mitochondria.
Insights
Inherited myopathies are linked to desmin mutations. This study shows low-level L345P desmin mutation impairs skeletal and cardiac muscle function, primarily impacting mitochondria.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Desmin mutations are associated with inherited myopathies and cardiomyopathies affecting skeletal and cardiac muscles.
- The severity and muscle involvement vary significantly among different desmin mutations.
Purpose of the Study:
- To investigate the effects of a low-level L345P desmin mutation on skeletal and cardiac muscle function.
- To elucidate the underlying mechanisms, particularly the role of mitochondria, in desmin-related muscle disorders.
Main Methods:
- Development of a transgenic mouse model (DESMUT mice) expressing a low level of the L345P desmin mutation.
- Ultrastructural analysis of muscle tissue to identify cellular changes.
- Measurement of mitochondrial calcium levels in myocytes.
- Assessment of contractile function and fatigue recovery in isolated soleus muscles.
- Neuromuscular performance evaluation using SHIRPA screening.
- Echocardiographic analysis to assess cardiac function.
Main Results:
- DESMUT mice exhibited significant mitochondrial swelling and vacuolization in skeletal and cardiac muscles.
- Elevated mitochondrial calcium levels were observed in myocytes from DESMUT mice during and after contractions.
- Impaired contractile function and reduced recovery from fatigue were noted in isolated DESMUT soleus muscles.
- Decreased motor function was evident in DESMUT mice compared to wild-type controls.
- Echocardiography revealed left ventricular hypertrophy and reduced chamber dimensions in DESMUT mice.
Conclusions:
- Low levels of the L345P desmin mutation induce significant ultrastructural and functional deficits in both skeletal and cardiac muscles.
- The observed muscle impairments are, at least partially, mediated by a dominant-negative effect of the mutant desmin on mitochondrial function.
- This mouse model provides valuable insights into the pathogenesis of desmin-related myopathies and cardiomyopathies.
