Repairing the defective folding of alpha-sarcoglycan is needed to promote myogenic cell engraftment in 3D artificial muscle models of LGMDR3.

Limb-girdle muscular dystrophy 2D (or LGMDR3) is a rare autosomal recessive disorder caused by mutations in the SGCA gene, which encode α-sarcoglycan (α-SG). α-SG is a critical component of the dystrophin-associated protein complex, whose role in differentiated muscle is to distribute contraction force and protect the sarcolemma from mechanical damage. Most SGCA mutations are missense, leading to a folding-defective α-SG that is degraded by the ubiquitin-proteasome system, destabilizing the sarcolemma and causing progressive muscle weakness. Notably, pharmacological restoration of α-SG function using cystic fibrosis transmembrane conductance regulator (CFTR) correctors, such as C17, can rescue the SG-complex, improving muscle strength in an LGMDR3 mouse model. Our initial aim was to generate 3D diaphragm-like models of LGMDR3 by seeding patient-derived myoblasts onto a decellularised diaphragm scaffold, thereby mimicking the disease environment and enabling drug screening beyond the limitations of 2D cultures. While the models did not behave as anticipated, the unexpected outcome led us to uncover a previously underappreciated role of α-SG. Specifically, we found that α-SG expressed by immature myoblasts is crucial for cell adhesion and migration, key processes for muscle development, regeneration, and successful engraftment into a decellularized extracellular matrix. These processes, compromised in LGMDR3 cells, can be rescued through CFTR correctors, further supporting their potential therapeutic application in LGMDR3.