Sonic hedgehog therapy in a mouse model of age-associated impairment of skeletal muscle regeneration

J Gerontol A Biol Sci Med Sci. 2014 Mar;69(3):245-52. doi: 10.1093/gerona/glt076. Epub 2013 Jun 18.


Sonic hedgehog (Shh) is a morphogen regulating muscle development during embryogenesis. We have shown that the Shh pathway is postnatally recapitulated after injury and during regeneration of the adult skeletal muscle and regulates angiogenesis and myogenesis after muscle injury. Here, we demonstrate that in 18-month-old mice, there is a significant impairment of the upregulation of the Shh pathway that physiologically occurs in the young skeletal muscle after injury. Such impairment is even more pronounced in 24-month-old mice. In old animals, intramuscular therapy with a plasmid encoding the human Shh gene increases the regenerative capacities of the injured muscle, in terms of Myf5-positive cells, regenerating myofibers, and fibrosis. At the molecular level, Shh treatment increases the upregulation of the prototypical growth factors, insulin-like growth factor-1 and vascular endothelial growth factor. These data demonstrate that Shh increases regeneration after injury in the muscle of 24-month-old mice and suggest that the manipulation of the Shh pathway may be useful for the treatment of muscular diseases associated with aging.

Keywords: Aging.; Skeletal muscle regeneration; Sonic hedgehog.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Cardiotoxins / toxicity
  • Disease Models, Animal
  • Fibrosis
  • Genetic Therapy / methods
  • Hedgehog Proteins / therapeutic use*
  • Humans
  • Insulin-Like Growth Factor I / drug effects
  • Intercellular Signaling Peptides and Proteins / analysis
  • Kruppel-Like Transcription Factors / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Muscle Development / drug effects
  • Muscle Development / physiology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / injuries*
  • Myofibrils / drug effects
  • Myogenic Regulatory Factor 5 / analysis
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology
  • Plasmids / genetics
  • Regeneration / drug effects*
  • Signal Transduction / drug effects
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / drug effects
  • Zinc Finger Protein GLI1


  • Cardiotoxins
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Intercellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Myf5 protein, mouse
  • Myogenic Regulatory Factor 5
  • SHH protein, human
  • Vascular Endothelial Growth Factor A
  • Zinc Finger Protein GLI1
  • vascular endothelial growth factor A, mouse
  • Insulin-Like Growth Factor I