Targeting Skeletal Muscle in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-Glucose Co-Transporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. We integrated open-access proteomic and transcriptomic datasets for in-silico analyses, including differential gene expression (DE), Weighted Gene Co-Expression Network Analysis (WGCNA), and pathway enrichment to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine datasets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg/day for 4 weeks starting at 12 weeks) and DMD mdx rats (10 mg/kg/day for 4 months starting at 5 months), with vehicle controls. Validation used RT-qPCR, grip-strength testing, and histological fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGF-β1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.