PUBLICATION
Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy
- Authors
- Li, M., Andersson-Lendahl, M., Sejersen, T., Arner, A.
- ID
- ZDB-PUB-160330-7
- Date
- 2016
- Source
- The Journal of general physiology 147: 309-22 (Journal)
- Registered Authors
- Lendahl, Monika Andersson, Li, Mei
- Keywords
- none
- MeSH Terms
-
- Actins/metabolism
- Animals
- Apoptosis
- Gene Deletion
- Muscular Diseases/genetics*
- Muscular Diseases/metabolism
- Sarcomeres/metabolism*
- Sarcomeres/pathology
- Skeletal Muscle Myosins/genetics
- Skeletal Muscle Myosins/metabolism*
- Zebrafish
- PubMed
- 27022191 Full text @ J. Gen. Physiol.
Citation
Li, M., Andersson-Lendahl, M., Sejersen, T., Arner, A. (2016) Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy. The Journal of general physiology. 147:309-22.
Abstract
Myosin-binding protein C (MyBPC) in the muscle sarcomere interacts with several contractile and structural proteins. Mutations in the cardiac isoform (MyBPC-3) in humans, or animal knockout, are associated with cardiomyopathy. Function of the fast skeletal isoform (MyBPC-2) in living muscles is less understood. This question was addressed using zebrafish models, combining gene expression data with functional analysis of contractility and small-angle x-ray diffraction measurements of filament structure. Fast skeletal MyBPC-2B, the major isoform, was knocked down by >50% using morpholino antisense nucleotides. These morphants exhibited a skeletal myopathy with elevated apoptosis and up-regulation of factors associated with muscle protein degradation. Morphant muscles had shorter sarcomeres with a broader length distribution, shorter actin filaments, and a wider interfilament spacing compared with controls, suggesting that fast skeletal MyBPC has a role in sarcomere assembly. Active force was reduced more than expected from the decrease in muscle size, suggesting that MyBPC-2 is required for optimal force generation at the cross-bridge level. The maximal shortening velocity was significantly increased in the MyBPC-2 morphants, but when related to the sarcomere length, the difference was smaller, reflecting that the decrease in MyBPC-2B content and the resulting myopathy were accompanied by only a minor influence on filament shortening kinetics. In the controls, equatorial patterns from small-angle x-ray scattering revealed that comparatively few cross-bridges are attached (as evaluated by the intensity ratio of the 11 and 10 equatorial reflections) during active contraction. X-ray scattering data from relaxed and contracting morphants were not significantly different from those in controls. However, the increase in the 11:10 intensity ratio in rigor was lower compared with that in controls, possibly reflecting effects of MyBPC on the cross-bridge interactions. In conclusion, lack of MyBPC-2 results in a severe skeletal myopathy with structural changes and muscle weakness.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping