Key result
mdx mice exhibit >500-fold higher urinary titin N-terminal fragments versus normal mice.
Why the study?
Urinary titin N-terminal fragment levels reflect muscle wasting in humans with DMD, but a highly sensitive ELISA kit for mouse urine had been awaited.
Effect estimate: >500-fold higher
A newly developed sandwich ELISA kit demonstrates that urinary titin N-terminal fragment levels are markedly elevated in mdx mice and decline with age, providing a potential biomarker for monitoring muscle protein breakdown in preclinical DMD studies.
May support titin as DMD biomarker in mdx models; leaves open human validation.
The mdx mouse is a model of Duchenne muscular dystrophy (DMD), a fatal progressive muscle wasting disease caused by dystrophin deficiency, and is used most widely in preclinical studies. Mice with dystrophin deficiency, however, show milder muscle strength phenotypes than humans. In human, the introduction of a sandwich enzyme-linked immunosorbent assay (ELISA) kit revealed a more than 700-fold increase in titin N-terminal fragment levels in the urine of pediatric patients with DMD. Notably, the urinary titin level declines with aging, reflecting progression of muscle wasting. In mouse, development of a highly sensitive ELISA kit has been awaited. Here, a sandwich ELISA kit to measure titin N-terminal fragment levels in mouse urine was developed. The developed kit showed good linearity, recovery, and repeatability in measuring recombinant or natural mouse titin N-terminal fragment levels. The titin N-terminal fragment concentration in the urine of mdx mice was more than 500-fold higher than that of normal mice. Urinary titin was further analyzed by extending the collection of urine samples to both young (3-11 weeks old) and aged (56-58 weeks old) mdx mice. The concentration in the young group was significantly higher than that in the aged group. It was concluded that muscle protein breakdown is active and persistent in mdx mice even though the muscle phenotype is mild. Our results provide an opportunity to develop DMD treatments that aim to alleviate muscle protein breakdown by monitoring urinary titin levels.
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Shirakawa et al. (2022) studied Duchenne muscular dystrophy (mdx mouse model). mdx genotype (Duchenne muscular dystrophy model) vs. Normal mice was evaluated on Urinary titin N-terminal fragment concentration (>500-fold higher). The titin N-terminal fragment concentration in the urine of mdx mice was more than 500-fold higher than that of normal mice, and significantly higher in young versus aged mdx mice.
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