Sarcospan selectively interfaces with sarcoglycan subunits to stabilize the sarcolemma and prevent limb-girdle muscular dystrophy

Skeletal muscle possesses redundant molecular mechanisms that partially or fully compensate for loss of gene function and this information has been leveraged for development of novel therapies for the muscular dystrophies. Mutations in any one of the canonical sarcoglycan genes cause autosomal recessive Limb-girdle muscular dystrophies that are characterized by life-limiting skeletal muscle wasting and weakness. The objective of this study was to investigate the orthologous relationships within the sarcoglycan proteins and use these mechanisms to design new therapies for the Limb-girdle muscular dystrophies. The sarcoglycan complex canonically consists of alpha-, beta-, delta- and gamma-subunits. We show that sarcospan, a transmembrane scaffolding protein, mediates assembly of a compensatory complex in gamma-sarcoglycan deficient muscles, where gamma-sarcoglycan is replaced by zeta-sarcoglycan, a less abundant sarcoglycan. This alternative complex significantly improved skeletal muscle pathology in mouse models of Limb-girdle muscular dystrophy. Three-dimensional structural modeling of the compensatory sarcoglycan complex reveals that zeta-sarcoglycan maintains specific hydrophobic interactions with sarcospan and preserves overall quaternary arrangement. This compensatory complex protects the cell membrane from contraction-induced damage and all secondary consequences of disease. These findings demonstrate a novel mechanism stabilizing the complex by leveraging protein redundancy, with an important role for sarcospan in assembly and scaffolding of a compensatory complex in skeletal muscles. This work is supported by Sarepta Therapeutics This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.