VMA21 is an endoplasmic reticulum chaperone protein essential for assembling the V0 complex of the vacuolar proton-transporting ATPase (V-ATPase), the primary proton pump required for lysosomal acidification 1. This function is critical across multiple cell types, including skeletal muscle where a muscle-specific VMA21-120 isoform is predominantly expressed and upregulated during muscle differentiation and development 2. VMA21 deficiency impairs V-ATPase assembly, causing lysosomal de-acidification and disabled autophagic degradation 3. This triggers compensatory macroautophagy, leading to accumulation of large, ineffective autolysosomes that vacuolate cells and cause tissue atrophy 1. VMA21 mutations cause X-linked myopathy with excessive autophagy (XMEA), a rare childhood-onset neuromuscular disorder characterized by progressive proximal muscle weakness, vacuolation, and elevated creatine kinase levels 4. Disease severity correlates with residual VMA21 protein expression 4. Beyond XMEA, VMA21 deficiency has been linked to congenital disorders of glycosylation with liver involvement, ER stress, and dysregulated lipid metabolism 5. VMA21 also plays roles in age-related neurodegeneration, with aerobic exercise improving autophagy-lysosomal flux through VMA21 upregulation in Alzheimer disease models 6.