Impaired Mitophagy Contributes to Pyroptosis in Sarcopenic Obesity Zebrafish Skeletal Muscle

<b>Background:</b> Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. <b>Methods:</b> In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 weeks to induce sarcopenic obesity. <b>Results:</b> After a dietary trial, HFD zebrafish exhibited an obese phenotype with skeletal muscle atrophy and decreased swimming capacity. We demonstrated that mitochondrial content and function were abnormal in SOB zebrafish skeletal muscle. These results may be associated with the impairment of mitophagy regulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin (PRKN) pathway. In addition, we also found that NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) signaling was activated with the upregulation of NLRP3, GSDMD-NT, and mature-IL1β, which indicated that pyroptosis was induced in SOB zebrafish skeletal muscle. <b>Conclusions:</b> Our study identified that impaired mitophagy and pyroptosis were associated with the pathogenesis of SOB. These results could potentially offer novel therapeutic objectives for the treatment of sarcopenic obesity.