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bioRxiv · 10.1101/2024.02.26.581979

Zebrafish and cellular models of SELENON-Related Myopathy exhibit novel embryonic and metabolic phenotypes

Barraza-Flores, P.·Moaghadaszadeh, B. S.·Lee, W.·Issac, B.·Sung, L.·Hickey, E.·Rockowitz, S.·Sliz, P.·Beggs, A. H.
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Abstract

SELENON-Related Myopathy (SELENON-RM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology commonly includes multiminicores or a dystrophic pattern but is often non-specific. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency causes SELENON-RM are undetermined. A hurdle is the lack of cellular and animal models that show assayable phenotypes. Here we report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression between selenon and genes involved in glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit changes in glutathione and redox homeostasis, suggesting a direct relationship with SelN function. We report changes in metabolic function abnormalities in SelN-null myotubes when compared to WT. These results suggest that SelN has functional roles during zebrafish early development and myoblast metabolism.

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Barraza-Flores, P., Moaghadaszadeh, B. S., Lee, W., Issac, B., Sung, L., Hickey, E., Rockowitz, S., Sliz, P., Beggs, A. H.. 2024-02-26. Zebrafish and cellular models of SELENON-Related Myopathy exhibit novel embryonic and metabolic phenotypes. https://doi.org/10.1101/2024.02.26.581979

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