Li, M., Andersson-Lendahl, M., Sejersen, T., and Arner, A. (2014) Muscle dysfunction and structural defects of dystrophin-null sapje mutant zebrafish larvae are rescued by ataluren treatment. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 34(Suppl2):116-122.
Sapje zebrafish carry a mutation in the dystrophin gene, which results in a premature stop codon, and a severe muscle phenotype.
They display several of the structural characteristics of Duchenne muscular dystrophy (DMD). Ataluren (PTC124) is proposed
to cause readthrough of premature stop codons and has been introduced as a potential treatment of genetic disorders. Clinical
trials in DMD have shown promise, although with complex dose dependency. We have established physiology techniques, enabling
high resolution of contractile function in skeletal muscle of zebrafish larvae. We aimed to provide a mechanical analysis
of sapje larval muscle and examine effects of ataluren. Homozygous 5 d postfertilization (dpf) sapje larvae exhibited structural defects with 50% decrease in active tension. Ataluren (0.1–1 μM, 3–5 dpf) improved contractile
function (<60% improvement of force at 0.5 μM) and dystrophin expression. Controls were not affected. Higher doses (5 μM,
35 μM) impaired contractile function, an effect also observed in controls, suggesting unspecific negative effects at high
concentrations. In summary, Sapje larvae exhibit impaired contractile performance and provide a relevant DMD model for functional studies. Ataluren significantly
improves skeletal muscle function in the sapje larvae, most likely reflecting an observed increase in dystrophin expression. The bell-shaped dose dependence in sapje resembles that previously reported in clinical DMD studies.—Li, M., Andersson-Lendahl, M., Sejersen, T., Arner, A. Muscle
dysfunction and structural defects of dystrophin-null sapje mutant zebrafish larvae are rescued by ataluren treatment.