HIGHLIGHTS ACROSS MYOLOGY: O.13 Altered calcium handling in a zebrafish model of SELENON congenital muscular dystrophy

Abstract

SELENON congenital muscular dystrophy (previously designated SEPN1 congenital muscular dystrophy) causes muscle weakness, scoliosis, and respiratory insufficiency in infants and children. Targeted treatments for this devastating disease are currently lacking. SELENON encodes the protein Selenoprotein N, a member of the selenoprotein family. Selenoprotein N is expressed at high levels in developing and immature tissues and adopts a ubiquitous, low-level expression pattern in mature tissues. This raises questions about how loss of Selenoprotein N leads to muscle-specific disease. Overlap in clinical and histopathologic characteristics between patients with SELENON congenital muscular dystrophy and certain types of RYR1 myopathy raise the possibility of interactions between Selenoprotein N and the RYR1 calcium channel. This possibility is supported by altered calcium release in SELENON-deficient myotubes in vitro but has not been tested in vivo. Here, calcium release was measured from Selenoprotein N-deficient zebrafish muscle fibers in vivo. Selenoprotein N-deficient zebrafish show decreased amplitude but increased frequency of calcium spikes during myogenesis with subsequent abnormal myofibril alignment in slow-twitch muscle fibers. Further, mature muscle fibers of Selenoprotein N-deficient zebrafish show decreased amplitude and duration of calcium release in response to depolarization compared to wildtype and control muscle fibers. The characteristics of calcium release in Selenoprotein N-deficient zebrafish muscle is suggestive of a leaky RYR1 calcium channel, as is typically seen in the setting of oxidative stress. These data support a role for Selenoprotein N in modulating RYR1 function in vivo, both during muscle development and during excitation-contraction coupling in mature muscle fibers.