Interferon-Associated Inflammatory Remodeling and Oxidative Metabolic Repression Define the Skeletal Muscle Transcriptomic Landscape of δ-Sarcoglycan Deficiency
Abstract
Limb-girdle muscular dystrophy R6, formerly LGMD2F, is caused by mutations in the δ-sarcoglycan (Sgcd) gene and is characterized by progressive skeletal muscle degeneration. Although loss of δ-SG protein compromises sarcolemma stability, how δ-sarcoglycan deficiency reshapes inflammatory and metabolic gene programs across distinct skeletal muscles remains incompletely defined. Here, we profiled soleus and extensor digitorum longus (EDL) muscles from wild-type and Sgcd−/− mice treated with vehicle or (-)-epicatechin, a dietary flavanol with anti-inflammatory and antioxidant properties, using bulk RNA sequencing, pathway analysis, immune-cell deconvolution, and RT-qPCR validation. δ-sarcoglycan deficiency produced broad transcriptional remodeling while preserving baseline muscle-type identity. Across soleus and EDL, the dystrophic transcriptome was marked by interferon-associated inflammatory remodeling together with repression of oxidative and mitochondrial metabolic programs. Within this shared disease state, soleus displayed a stronger induced inflammatory component, including innate-sensing and macrophage-linked features. Computational deconvolution, which estimates immune-cell proportions from bulk transcriptomes (quanTIseq and mMCP-counter), supported genotype-dependent shifts in immune-cell signatures, with concordant monocyte/macrophage signals. Finally, (-)-epicatechin produced context-dependent transcriptional effects and attenuated a defined interferon/innate-sensing module in dystrophic soleus, as supported by RNA-seq and RT-qPCR. Together, these findings establish inflammatory remodeling with a prominent interferon component and oxidative metabolic repression as central transcriptional features of δ-sarcoglycan-deficient skeletal muscle, while revealing an amplified innate-sensing and immune-enriched module in dystrophic soleus that remains transcriptionally responsive to (-)-epicatechin treatment.