Nonsense readthrough by ataluren prevents physical functional decline in aged dysferlinopathy mouse model

Background Dysferlinopathy is a progressive muscular dystrophy frequently caused by nonsense variants in the dysferlin gene. Our previous study demonstrated that the nonsense readthrough agent ataluren improves physical function in an early-stage dysferlinopathy model of 9 weeks old. Its therapeutic impact on more advanced stages remains unanswered. This study evaluates the efficacy of ataluren in 30-week-old dqx ^Dysf−/− mice harboring p.Q832* nonsense variant comparable to the adult stage of human dysferlinopathy. Methods Thirty-week-old dqx ^Dysf−/− mice were treated with ataluren over a 16-week period. Efficacy was evaluated longitudinally through serial physical function tests. Sarcolemmal protection against eccentric contraction was assessed. Restoration of dysferlin in skeletal muscle as well as molecular and histopathological changes were analyzed. Results Ataluren treatment successfully stabilized motor function in aged dqx ^Dysf−/− mice, most notably preventing the progressive decline in treadmill running distance observed in non-treated controls. Ataluren-treated mice also performed better in grip strength, rotarod, and autonomous movements. Ex vivo analysis showed that ataluren significantly attenuated decrements in contractile force following repetitive eccentric contractions, indicating protected sarcolemmal integrity. Ataluren restored sarcolemmal dysferlin expression to 11.2% of wild-type levels. Histopathological changes were not mitigated while we could observe restoration of myosin heavy chains and reversal of C/EBPα expression. Conclusions Ataluren induces nonsense readthrough and restores dysferlin in skeletal muscle moderately. This prevents physical functional decline in the aged dysferlinopathy mice model and protects sarcolemmal fragility, while the efficacy is less pronounced than in younger mice. These findings suggest that ataluren possesses significant therapeutic potential to mitigate disease progression even in the later, more advanced stages of dysferlin-deficient muscular dystrophies.