Development of a nitric oxide-releasing analogue of the muscle relaxant guaifenesin for skeletal muscle satellite cell myogenesis

Mol Pharm. May-Jun 2009;6(3):895-904. doi: 10.1021/mp800226z.

Abstract

Nitric oxide (NO) mediates activation of satellite precursor cells to enter the cell cycle. This provides new precursor cells for skeletal muscle growth and muscle repair from injury or disease. Targeting a new drug that specifically delivers NO to muscle has the potential to promote normal function and treat neuromuscular disease, and would also help to avoid side effects of NO from other treatment modalities. In this research, we examined the effectiveness of the NO donor, iosorbide dinitrate (ISDN), and a muscle relaxant, methocarbamol, in promoting satellite cell activation assayed by muscle cell DNA synthesis in normal adult mice. The work led to the development of guaifenesin dinitrate (GDN) as a new NO donor for delivering nitric oxide to muscle. The results revealed that there was a strong increase in muscle satellite cell activation and proliferation, demonstrated by a significant 38% rise in DNA synthesis after a single transdermal treatment with the new compound for 24 h. Western blot and immunohistochemistry analyses showed that the markers of satellite cell myogenesis, expression of myf5, myogenin, and follistatin, were increased after 24 h oral administration of the compound in adult mice. This research extends our understanding of the outcomes of NO-based treatments aimed at promoting muscle regeneration in normal tissue. The potential use of such treatment for conditions such as muscle atrophy in disuse and aging, and for the promotion of muscle tissue repair as required after injury or in neuromuscular diseases such as muscular dystrophy, is highlighted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Electron Spin Resonance Spectroscopy
  • Follistatin / metabolism
  • Guaifenesin / analogs & derivatives*
  • Guaifenesin / chemistry*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Muscle Development / drug effects*
  • Myogenic Regulatory Factor 5 / metabolism
  • Myogenin / metabolism
  • Neuromuscular Agents / chemistry*
  • Nitrates / chemistry*
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / chemical synthesis*
  • Nitric Oxide Donors / chemistry
  • Nitric Oxide Donors / pharmacology*
  • Satellite Cells, Skeletal Muscle / drug effects*
  • Satellite Cells, Skeletal Muscle / metabolism

Substances

  • Follistatin
  • Myf5 protein, mouse
  • Myogenic Regulatory Factor 5
  • Myogenin
  • Neuromuscular Agents
  • Nitrates
  • Nitric Oxide Donors
  • guaifenesin dinitrate
  • Nitric Oxide
  • Guaifenesin