Targeting Skeletal Muscle in Duchenne Muscular Dystrophy: Integrating in Silico and Experimental Approaches to Sodium-Glucose Cotransporter-2 Inhibition
Abstract
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 cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMDmdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. 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…
Read the paper
Related studies
- Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol
- Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance
- SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism
- Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors
- Sodium-glucose cotransporter inhibitors: beyond glycaemic control
- Decoding the effects of SGLT2 inhibitors on cardiac arrhythmias in heart failure
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.