Interactions among ryanodine receptor isotypes contribute to muscle fiber type development and function

Dis Model Mech. 2019 Sep 18;13(2):dmm038844. doi: 10.1242/dmm.038844.


Mutations affecting ryanodine receptor (RyR) calcium release channels commonly underlie congenital myopathies. Although these channels are known principally for their essential roles in muscle contractility, mutations in the human RYR1 gene result in a broad spectrum of phenotypes, including muscle weakness, altered proportions of fiber types, anomalous muscle fibers with cores or centrally placed nuclei, and dysmorphic craniofacial features. Currently, it is unknown which phenotypes directly reflect requirements for RyRs and which result secondarily to aberrant muscle function. To identify biological processes requiring RyR function, skeletal muscle development was analyzed in zebrafish embryos harboring protein-null mutations. RyR channels contribute to both muscle fiber development and function. Loss of some RyRs had modest effects, altering muscle fiber-type specification in the embryo without compromising viability. In addition, each RyR-encoding gene contributed to normal swimming behavior and muscle function. The RyR channels do not function in a simple additive manner. For example, although isoform RyR1a is sufficient for muscle contraction in the absence of RyR1b, RyR1a normally attenuates the activity of the co-expressed RyR1b channel in slow muscle. RyR3 also acts to modify the functions of other RyR channels. Furthermore, diminished RyR-dependent contractility affects both muscle fiber maturation and craniofacial development. These findings help to explain some of the heterogeneity of phenotypes that accompany RyR1 mutations in humans.

Keywords: Congenital myopathy; Muscle development; Muscle function; Ryanodine receptors; Zebrafish disease model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Behavior, Animal
  • Calcium Signaling
  • Embryo, Nonmammalian / metabolism
  • Face / embryology
  • Morphogenesis
  • Muscle Contraction
  • Muscle Fibers, Skeletal / metabolism*
  • Mutation / genetics
  • Protein Binding
  • Reflex, Startle
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Skull / embryology
  • Swimming
  • Zebrafish / embryology
  • Zebrafish / metabolism*
  • Zebrafish Proteins / metabolism


  • Ryanodine Receptor Calcium Release Channel
  • Zebrafish Proteins