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Published on: December 13, 2013
MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis
Kyungsoo Ha1, Jillian G Buchan, David M Alvarado
1Department of Orthopaedic Surgery.
Abstract:
Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
Insights
Myosin-binding protein C1 (MYBPC1) is crucial for embryonic motor activity and survival. MYBPC1 mutations cause arthrogryposis, impacting slow skeletal muscle development in zebrafish.
Area of Science:
- Muscle physiology
- Developmental biology
- Genetics
Background:
- Myosin-binding protein C1 (MYBPC1) is abundant in slow-twitch skeletal muscle fibers.
- Mutations in human MYBPC1 are linked to distal arthrogryposis and lethal congenital contracture syndrome.
- The precise function of MYBPC1 and the mechanism of associated contractures remain unclear.
Purpose of the Study:
- To investigate the role of MYBPC1 in embryonic development and motor function.
- To establish a zebrafish model for studying human MYBPC1 mutations and arthrogryposis.
- To elucidate the impact of specific human MYBPC1 mutations on embryonic development.
Main Methods:
- Antisense morpholino knockdown of mybpc1 in zebrafish embryos.
- Assessment of embryonic motor activity, survival, and physical development.
- Microscopic analysis of myofibril organization and sarcomere structure.
- Injection of MYBPC1 mRNAs with human distal arthrogryposis mutations into zebrafish embryos.
Main Results:
- Mybpc1 knockdown led to impaired embryonic motor activity, reduced survival, and severe body curvature in zebrafish.
- Slow skeletal muscle myofibril organization was impaired, with reduced sarcomere numbers in morphant embryos.
- Human MYBPC1 mutations (W236R, Y856H) exhibited dominant-negative effects, causing mild developmental defects and reduced survival.
Conclusions:
- MYBPC1 is essential for embryonic motor activity and survival, particularly in slow skeletal muscle development.
- Zebrafish serve as a viable model for understanding the pathogenesis of human distal arthrogryposis caused by MYBPC1 mutations.
- The study highlights the critical role of MYBPC1 in muscle development and provides insights into the mechanisms underlying congenital contracture syndromes.
