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Nitric oxide controls fat deposition in dystrophic skeletal muscle by regulating fibro-adipogenic precursor

Nicoletta Cordani1, Viviana Pisa, Laura Pozzi

  • 1Scientific Institute, IRCCS E. Medea 23842 Bosisio Parini, Lecco, Italy.

Stem Cells (Dayton, Ohio)
|October 31, 2013
PubMed

Insights

Nitric oxide (NO) inhibits fat and fibrosis development in Duchenne muscular dystrophy (DMD) by regulating fibro-adipogenic progenitors. This finding supports NO-based therapies for DMD by revealing a new mechanism beyond muscle regeneration.

Area of Science:

  • Muscle biology
  • Cellular and molecular medicine
  • Regenerative medicine

Background:

  • Duchenne muscular dystrophy (DMD) involves muscle fiber loss and replacement by fat and fibrous tissue.
  • Fibro-adipogenic progenitors (FAPs) expressing PDGFRα contribute to fibrosis and adipogenesis in dystrophic muscles.
  • Nitric oxide (NO) therapies slow DMD progression by enhancing muscle regeneration.

Purpose of the Study:

  • To investigate whether nitric oxide (NO) inhibits fibrosis and adipogenesis in Duchenne muscular dystrophy (DMD).
  • To elucidate the mechanism by which NO affects fibro-adipogenic progenitor (FAP) cell fate.

Main Methods:

  • In vitro studies on FAP differentiation.
  • In vivo studies using mdx mice (an animal model of DMD) treated with the NO-donating drug molsidomine.
  • Analysis of PDGFRα(+) cell counts, fat and connective tissue deposition.
  • Investigation of microRNA (miR-27b) and gene expression (Pparγ1).

Main Results:

  • In vitro, NO inhibited FAP differentiation into adipocytes.
  • Molsidomine treatment in mdx mice reduced PDGFRα(+) cells, skeletal muscle fat, and connective tissue.
  • NO-induced adipogenesis inhibition involved increased miR-27b expression, leading to Pparγ1 downregulation.
  • This pathway was independent of cGMP generation.

Conclusions:

  • Nitric oxide (NO) possesses an additional therapeutic effect in Duchenne muscular dystrophy (DMD) by inhibiting fibrosis and adipogenesis.
  • NO regulates FAP fate, reducing fat and connective tissue accumulation in dystrophic muscles.
  • These findings provide a mechanistic basis for the efficacy of NO-based therapies in DMD, complementing their known regenerative effects.
Keywords:
AdipocytesFibro-adipogenic precursorsFibrosisMicroRNANitric oxideSkeletal muscle dystrophy

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