Abstract
Limb-girdle muscular dystrophy 2G (LGMD2G) is a subtype of limb-girdle muscular dystrophy. However, the disease’s mechanisms are still not fully understood, and no established therapeutic targets have been found. Using a morpholino-based knockdown approach, we established an LGMD2G zebrafish model. In this study, we found that the ROS level increased in LGMD2G zebrafish. The expression of the mitophagy-related protein BNIP3L, LC3A-II/LC3A-I, and LAMP1 were increased in LGMD2G zebrafish. The oxygen consumption rate and citrate synthase expression was significantly decreased. Thus, mitophagy was presumed to be involved in the LGMD2G to reduce ROS levels. Then, we administered vitamin C, coenzyme Q10, idebenone, metformin, or dexamethasone to rescue LGMD2G in zebrafish. Idebenone reduced the curly tail phenotype and ROS level. Also, it reduced BNIP3L expression in LGMD2G zebrafish models and improved their motor function. In conclusion, mitophagy might be involved in the LGMD2G, and idebenone ameliorated LGMD2G by downregulating ROS level.
Highlights
Limb-girdle muscular dystrophy 2G (LGMD2G) is a subtype of limb-girdle muscular dystrophy caused by nonsense or frameshift mutations in TCAP (Lv et al, 2020)
The most interesting finding is that we observe abnormal mitochondria distribution, which is illustrated by the presence of high enzyme activities for NADH, succinate dehydrogenase (SDH), and c oxidase (COX) staining at the periphery of sarcoplasm and the decreased enzyme activities in the center of sarcoplasm (Figures 1C–E)
Autophagy insufficiency induced by the knockout of autophagy/mitophagy-related genes causes a significant increase in cellular reactive oxygen species (ROS), suggesting that ROS are liberated from damaged mitochondria that escape mitophagy
Summary
Limb-girdle muscular dystrophy 2G (LGMD2G) is a subtype of limb-girdle muscular dystrophy caused by nonsense or frameshift mutations in TCAP (Lv et al, 2020). TCAP encodes telethonin, a 19 kD protein located in the periphery of Z-discs (Zhang et al, 2009). Studies examining the pathogenesis of LGMD2G are rare. In 2009, Zhang and his colleagues reported disrupted formation of the T-tubule system in LGMD2G zebrafish models (Zhang et al, 2009). Their study indicated that stretch force induces variable expression, and tcap expression is negatively regulated by integrin-link kinase. In 2010, a tcap knockout mouse model was generated and showed a dystrophic phenotype comparable to that of patients with LGMD2G (Markert et al, 2010). In 2013, Ibrahim et al reported another mouse model. They investigated this gene function in cardiomyocytes, suggesting that telethonin is a critical, load sensitive regulator of t-tubule structure and function (Ibrahim et al, 2013). The disease’s mechanisms are still not fully understood, and no established therapeutic targets have been found
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