In this study,we presented a novel zebrafish mutantcas6,carrying recessive mutation in arfgap2 gene,exhibited severe muscular defect,exemplified by disruption of sarcolemma integrity,myofibril organization and T-tubule,with emergent inflammatory response in dystrophic skeletal muscle.We found that muscle-specific overexpression of Caveolin3P104L,a mutant form of Cav3 discovered in Caveolinopathy patients,could recapitulate the muscular and inflammatory phenotype in arfgap2cas6 mutant.Furthermore,we demonstrated ARFAGP2 is required for Cav3 sarcolemma localization in zebrafish embryos or in mouse C2C12 myoblast cells.Collectively,this study demonstrated a novel and vital role of ARFGAP2 in sarcolemma integrity maintenance through regulating subcellular localization of Cav3.