Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP

Stem Cells. 2012 Feb;30(2):197-209. doi: 10.1002/stem.783.


Satellite cells are myogenic precursors that proliferate, activate, and differentiate on muscle injury to sustain the regenerative capacity of adult skeletal muscle; in this process, they self-renew through the return to quiescence of the cycling progeny. This mechanism, while efficient in physiological conditions does not prevent exhaustion of satellite cells in pathologies such as muscular dystrophy where numerous rounds of damage occur. Here, we describe a key role of nitric oxide, an important signaling molecule in adult skeletal muscle, on satellite cells maintenance, studied ex vivo on isolated myofibers and in vivo using the α-sarcoglycan null mouse model of dystrophy and a cardiotoxin-induced model of repetitive damage. Nitric oxide stimulated satellite cells proliferation in a pathway dependent on cGMP generation. Furthermore, it increased the number of Pax7(+)/Myf5(-) cells in a cGMP-independent pathway requiring enhanced expression of Vangl2, a member of the planar cell polarity pathway involved in the Wnt noncanonical pathway. The enhanced self-renewal ability of satellite cells induced by nitric oxide is sufficient to delay the reduction of the satellite cell pool during repetitive acute and chronic damages, favoring muscle regeneration; in the α-sarcoglycan null dystrophic mouse, it also slowed disease progression persistently. These results identify nitric oxide as a key messenger in satellite cells maintenance, expand the significance of the Vangl2-dependent Wnt noncanonical pathway in myogenesis, and indicate novel strategies to optimize nitric oxide-based therapies for muscular dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cyclic GMP / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Mice
  • Mice, 129 Strain
  • Molsidomine / pharmacology
  • Molsidomine / therapeutic use
  • Muscle Development / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / embryology
  • Muscle, Skeletal / physiology*
  • Muscular Dystrophies / drug therapy
  • Muscular Dystrophies / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nitric Oxide / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Donors / therapeutic use
  • Regeneration*
  • Satellite Cells, Skeletal Muscle / drug effects
  • Satellite Cells, Skeletal Muscle / metabolism
  • Satellite Cells, Skeletal Muscle / physiology*
  • Signal Transduction


  • Ltap protein, mouse
  • Nerve Tissue Proteins
  • Nitric Oxide Donors
  • Nitric Oxide
  • Molsidomine
  • Cyclic GMP