2. Academic Validation
  3. Targeting Skeletal Muscle in Duchenne Muscular Dystrophy: Integrating in Silico and Experimental Approaches to Sodium-Glucose Cotransporter-2 Inhibition

Targeting Skeletal Muscle in Duchenne Muscular Dystrophy: Integrating in Silico and Experimental Approaches to Sodium-Glucose Cotransporter-2 Inhibition

  • Am J Pathol. 2025 Dec 13:S0002-9440(25)00433-X. doi: 10.1016/j.ajpath.2025.11.002.
Christopher Dostal 1,  Johanna Reiner 2,  Ana Isabel Antunes Goncalves 3,  Laura Silva Sousa 3,  Marlene Knapp 3,  Joel Fischlein 3,  Jessica Marksteiner 4,  Jakob Sauer 4,  Gavin Y Oudit 5,  Anja Wagner 6,  Dietmar Abraham 7,  Karlheinz Hilber 4,  Klaus Kratochwill 8,  Bruno K Podesser 9,  Attila Kiss 10
Affiliations

Affiliations

  • 1 Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria; CBRS Center for Bioinformatic Research and Services e.U., Vienna, Austria.
  • 2 Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria; CBRS Center for Bioinformatic Research and Services e.U., Vienna, Austria; Ludwig Boltzman Institute for Cardiovascular Research, Vienna, Austria.
  • 3 Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria.
  • 4 Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 5 Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
  • 6 Core Facility Proteomics, Medical University of Vienna, Vienna, Austria.
  • 7 Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
  • 8 Core Facility Proteomics, Medical University of Vienna, Vienna, Austria; Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
  • 9 Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria; Ludwig Boltzman Institute for Cardiovascular Research, Vienna, Austria.
  • 10 Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria; Ludwig Boltzman Institute for Cardiovascular Research, Vienna, Austria. Electronic address: [email protected].
PMID: 41391749 DOI: 10.1016/j.ajpath.2025.11.002
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 RT-qPCR, 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 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.

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