ZFIN ID: ZDB-PUB-160330-7
Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy
Li, M., Andersson-Lendahl, M., Sejersen, T., Arner, A.
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.
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.