Biological scaffold-mediated delivery of myostatin inhibitor promotes a regenerative immune response in an animal model of Duchenne muscular dystrophy

J Biol Chem. 2018 Oct 5;293(40):15594-15605. doi: 10.1074/jbc.RA118.004417. Epub 2018 Aug 23.


Recent studies have reported that the immune system significantly mediates skeletal muscle repair and regeneration. Additionally, biological scaffolds have been shown to play a role in polarizing the immune microenvironment toward pro-myogenic outcomes. Moreover, myostatin inhibitors are known to promote muscle regeneration and ameliorate fibrosis in animal models of Duchenne muscular dystrophy (DMD), a human disease characterized by chronic muscle degeneration. Biological scaffolds and myostatin inhibition can potentially influence immune-mediated regeneration in the dystrophic environment, but have not been evaluated together. Toward this end, here we created an injectable biological scaffold composed of hyaluronic acid and processed skeletal muscle extracellular matrix. This material formed a cytocompatible hydrogel at physiological temperatures in vitro When injected subfascially above the tibialis anterior muscles of both WT and dystrophic mdx-5Cv mice, a murine model of DMD, the hydrogel spreads across the entire muscle before completely degrading at 3 weeks in vivo We found that the hydrogel is associated with CD206+ pro-regenerative macrophage polarization and elevated anti-inflammatory cytokine expression in both WT and dystrophic mice. Co-injection of both hydrogel and myostatin inhibitor significantly increased FoxP3+ regulatory T cell modulation and Foxp3 gene expression in the scaffold immune microenvironment. Finally, delivery of myostatin inhibitor with the hydrogel increased its bioactivity in vivo, and transplantation of immortalized human myoblasts with the hydrogel promoted their survival in vivo This study identifies a key role for biological scaffolds and myostatin inhibitors in modulating a pro-regenerative immune microenvironment in dystrophic muscle.

Keywords: bioengineering; biomaterials; cytokine; drug delivery; dystrophin; extracellular matrix; hydrogel; immunology; mdx; muscle; muscle regeneration; muscular dystrophy; myostatin; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorbable Implants
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Drug Delivery Systems / methods*
  • Extracellular Matrix / chemistry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression Regulation
  • Humans
  • Hyaluronic Acid / chemistry
  • Hydrogels / chemistry
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mannose Receptor
  • Mannose-Binding Lectins / genetics
  • Mannose-Binding Lectins / immunology
  • Mice
  • Mice, Inbred mdx
  • Muscle Development / drug effects
  • Muscle Development / genetics
  • Muscle Development / immunology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Animal / drug therapy*
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / immunology
  • Muscular Dystrophy, Animal / pathology
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / immunology
  • Myostatin / antagonists & inhibitors*
  • Myostatin / genetics
  • Myostatin / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Regeneration / drug effects*
  • Regeneration / genetics
  • Regeneration / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Tissue Scaffolds


  • Antibodies, Monoclonal
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hydrogels
  • Lectins, C-Type
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Mstn protein, mouse
  • Myostatin
  • Receptors, Cell Surface
  • Hyaluronic Acid