Zhilong Zhang

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy.

Hypertrophic cardiomyopathy (HCM) is a relatively common global cardiac disease, usually inherited, with complex phenotypes, genetic features, and a natural history. In this study, we constructed atic^−/− zebrafish using the CRISPR/Cas9 gene-editing system and found that atic^−/− zebrafish hearts exhibited HCM symptoms, and atic^−/− zebrafish hearts showed progressive enlargement, eccentric hypertrophy, cardiomyocyte enlargement, and collagen fiber deposition. Echocardiography results also showed that compared with atic^−/− zebrafish hearts, in wild-type zebrafish hearts, the ejection fraction was significantly reduced, shortening fraction was reduced, and ventricular wall thickness was significantly increased. Meanwhile, aerobic exercise intervention in atic^−/− zebrafish showed that aerobic exercise effectively improved the symptoms of HCM and improved cardiac function in atic^−/− zebrafish hearts. Transcriptome sequencing results showed that aerobic exercise improved the symptoms of HCM in atic^−/− zebrafish hearts involving the calcium signaling pathway, Apelin signaling pathway and ECM–receptor interaction. The q-PCR results of key differential genes involved in these pathways further confirmed that aerobic exercise could bring beneficial effects to atic^−/− zebrafish. In conclusion, this study found that the loss of ATIC can lead to hypertrophic cardiomyopathy in zebrafish, and aerobic exercise intervention can effectively improve the hypertrophic pathological characteristics of atic^−/− zebrafish hearts, providing new intervention targets and effective lifestyle interventions for HCM.