In vivo evidence for altered excitation-contraction coupling in a zebrafish model of SELENON congenital muscular dystrophy


Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 207


Melissa Wright, MD, PhD


1. University of Colorado Denver

SELENON congenital muscular dystrophy (previously designated SEPN1 congenital muscular dystrophy) is characterized by axial weakness and poor head control in infancy, with spinal rigidity in early childhood progressing to scoliosis in early adolescence, and early onset of respiratory impairment. SELENON belongs to a group of proteins called selenoproteins, many of which are known to participate in redox reactions. It is not clear how loss of SELENON leads to a muscle specific phenotype as it has a nearly ubiquitous expression pattern. However, overlap in both clinical and histopathologic characteristics between SELENON congenital muscular dystrophy and the autosomal recessive RYR1 myopathy, multiminicore myopathy, raises the possibility of interactions between SELENON and RYR1. This would disrupt myofiber development and organization and would alter excitation-contraction coupling in mature myofibers. In vitro studies support a physical interaction between SELENON and RYR. Further, SELENON-deficient myotubes show altered calcium release in response to chemical stimuli. However, the role of SELENON in calcium release from myofibers in vivo has not been demonstrated.

The objective of this study is to evaluate the effect of loss of SELENON on stimulus-dependent calcium release in a zebrafish model of SELENON congenital muscular dystrophy.

The optical transparency of zebrafish larvae allows measurement of calcium transients from individual muscle fibers in vivo using fluorescent calcium indicator dyes. Here, calcium release was measured from muscle fibers in vivo in a zebrafish model of SELENON congenital muscular dystrophy. Selenon deficient zebrafish larvae show decreased swimming velocity and decreased amplitude and duration of muscle calcium transients during touch-evoked fictive swimming compared to wildtype controls.

This work provides further evidence for altered RYR1 function in SELENON-related congenital muscular dystrophy.