Sarcoglycanopathy represents an autosomal recessive limb-girdle muscular dystrophy (LGMD), caused by mutations in sarcoglycans (SGCs). Individual SGC forms the complex within the endoplasmic reticulum (ER) prior to reaching the sarcolemma. Human patients with mutations in SGCs often exhibit a reduced or complete loss of the SGC complex, highlighting the importance of its folding in the ER. Protein quality control systems, such as autophagy and unfolded protein response (UPR), play critical roles in maintaining skeletal muscle homeostasis and are required to preserve muscle function under conditions of muscular dystrophy. SEL1L-HRD1 endoplasmic reticulum associated degradation (ERAD) complex represents the most conserved ERAD branch, responsible for the recognition, recruitment, retrotranslocation and ubiquitination of misfolded ER proteins. However, the role of ERAD, another principal protein quality control machinery, in muscular dystrophy is largely unknown. Skeletal myocyte-specific SEL1L knockout mice exhibit fiber size variation and progressive muscle weakness, characterized by kyphosis and increased central nuclei in skeletal muscle particularly in proximal muscles (similar to the development of LGMD in humans). An unbiased screen identified SGCB as a potential ERAD substrate. Interestingly, we observed the accumulation of SGCs in the sarcolemma in skeletal myocyte-specific SEL1L knockout mice. Therefore, the data suggest that SEL1L-HRD1 ERAD plays a key role in sarcoglycanopathy by regulating the abundance of SGCs. This study will help identify potential therapeutic targets for sarcoglycanopathy.