Nuclear Deformities Minimally Affect Fiber-Type-Specific Disease Progression in Murine Models of Nuclear Envelope
Eiji Wada1, Nao Susumu1, Yukiko K Hayashi1
1Department of Pathophysiology, Tokyo Medical University, Tokyo, Japan.
Abstract:
Abnormalities in nuclear morphology are specific features of the nuclear envelopathies, including Emery-Dreifuss muscular dystrophy (EDMD). The presence of abnormally shaped nuclei in the skeletal muscles of EDMD patients and murine models has been reported both in vivo and in vitro; however, how the presence of nuclear architectural abnormalities affects disease development and progression remains unclear. In this study, we analyzed slow-twitch soleus (SOL) muscles and fast-twitch extensor digitorum longus (EDL) muscles from the following EDMD model mice: emerin knockout (Emd), LmnaH222P/H222P knockin (H222P), and Emd/H222P double-mutated (EH), to elucidate the effects of altered nuclear shapes on fiber-type-specific disease development. Dystrophic phenotypes were exclusively detected in the SOL muscles of EH mice, and myonuclear shape irregularities were observed only in the SOL muscle but not in the EDL muscle. Recovery from cardiotoxin (CTX) injection improved the shapes of peripheral myonuclei, and muscle histology and function, concomitant with an increase in the number and size of type 1 fibers in the regenerated SOL muscles of EH mice 42 days after the muscle damage. Importantly, nuclear morphology was relatively retained even after 126 days from the CTX injection, although dystrophic pathology gradually progressed. Taken together, our results indicate that the presence of nuclear morphological changes plays a minor role in the fiber-type-specific progression of muscular dystrophy in EDMD.
Insights
Nuclear shape abnormalities in Emery-Dreifuss muscular dystrophy (EDMD) appear to play a minor role in disease progression. Studies on EDMD model mice suggest that altered nuclear morphology does not significantly drive fiber-type-specific muscular dystrophy.
Area of Science:
- Muscle Biology
- Cellular Morphology
- Genetic Diseases
Background:
- Nuclear envelopathies, such as Emery-Dreifuss muscular dystrophy (EDMD), are characterized by abnormal nuclear morphology.
- The impact of these nuclear architectural abnormalities on disease development and progression in skeletal muscle remains largely unknown.
Purpose of the Study:
- To investigate the role of altered nuclear shapes in fiber-type-specific disease development in mouse models of EDMD.
- To analyze the relationship between nuclear morphology and dystrophic phenotypes in different muscle fiber types.
Main Methods:
- Analysis of slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) muscles from emerin knockout (Emd), LmnaH222P/H222P knockin (H222P), and Emd/H222P double-mutated (EH) EDMD model mice.
- Assessment of myonuclear shape irregularities and dystrophic phenotypes.
- Evaluation of muscle recovery and nuclear morphology following cardiotoxin (CTX) injection.
Main Results:
- Dystrophic phenotypes were exclusively observed in the SOL muscles of EH mice, with myonuclear shape irregularities also limited to SOL muscle.
- Recovery from CTX injection improved myonuclear shape, muscle histology, and function, with an increase in type 1 fibers in regenerated SOL muscles.
- Nuclear morphology was largely retained post-injury, despite gradual progression of dystrophic pathology.
Conclusions:
- Nuclear morphological changes play a minor role in the fiber-type-specific progression of muscular dystrophy in EDMD.
- The study elucidates the complex interplay between nuclear architecture and muscle disease, highlighting fiber-type specificity.
