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

ABSTRACT: Gene duplication events provide redundancy to complex organisms, and homologous genes and their encoded proteins are potential replacements to treat loss-of-function genetic syndromes. Skeletal muscle possesses redundant molecular mechanisms that partially or fully compensate for loss of gene function. Within the dystrophin-glycoprotein complex (DGC), utrophin is known to substitute for dystrophin. However, there has been little investigation of the orthologous relationships within the sarcoglycan subcomplex of the DGC. In skeletal muscle, the sarcoglycan complex canonically consists of alpha-, beta-, gamma- and delta-subunits, with gamma- and delta-sarcoglycan showing the greatest homology but no functional redundancy. We show that sarcospan, a transmembrane scaffolding protein, mediates assembly of a compensatory DGC with gamma-sarcoglycan replacement by zeta-sarcoglycan. This alternative complex improved pathology ingamma-sarcoglycan muscular dystrophy, but not alpha- or beta-sarcoglycan muscular dystrophy where sarcospan was unable to form compensatory complexes. Three-dimensional modeling of the compensatory DGC reveals that zeta-sarcoglycan maintains specific hydrophobic interactions with sarcospan and preserves overall quaternary arrangement. This compensatory DGC protects the cell membrane from contraction-induced damage and all secondary consequences of disease. These findings demonstrate a novel mechanism stabilizing the DGC by leveraging protein redundancy, with an important role for sarcospan in assembly and scaffolding of a compensatory DGC.

ORGANISM(S): Mus musculus

PROVIDER: GSE291423 | GEO | 2025/06/01

REPOSITORIES: GEO

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Project description:Background: The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury. In this study, we utilized transcriptomic and ECM protein-optimized proteomics data sets from wild-type, mdx, and mdx transgenic (mdxTG) skeletal muscle tissues to identify pathways and proteins driving the compensatory action of SSPN overexpression. Methods: The tibialis anterior and quadriceps muscles were isolated from wild-type, mdx, and mdxTG mice and subjected to bulk RNA-Seq and global proteomics analysis using methods to enhance capture of ECM proteins. Data sets were further analyzed through the ingenuity pathway analysis (QIAGEN) and integrative gene set enrichment to identify candidate networks, signaling pathways, and upstream regulators. Results: Through our multi-omics approach, we identified 3 classes of differentially expressed genes and proteins in mdxTG muscle, including those that were (1) unrestored (significantly different from wild type, but not from mdx), (2) restored (significantly different from mdx, but not from wild type), and (3) compensatory (significantly different from both wild type and mdx). We identified signaling pathways that may contribute to the rescue phenotype, most notably cytoskeleton and ECM organization pathways. ECM-optimized proteomics revealed an increased abundance of collagens II, V, and XI, along with β-spectrin in mdxTG samples. Using ingenuity pathway analysis, we identified upstream regulators that are computationally predicted to drive compensatory changes, revealing a possible mechanism of SSPN rescue through a rewiring of cell-ECM bidirectional communication. We found that SSPN overexpression results in upregulation of key signaling molecules associated with regulation of cytoskeleton organization and mechanotransduction, including Yap1, Sox9, Rho, RAC, and Wnt. Conclusions: Our findings indicate that SSPN overexpression rescues dystrophin deficiency partially through mechanotransduction signaling cascades mediated through components of the ECM and the cortical cytoskeleton.

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

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