Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy

Curr Opin Clin Nutr Metab Care. 2015 May;18(3):263-8. doi: 10.1097/MCO.0000000000000159.

Abstract

Purpose of review: Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy.

Recent findings: Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function.

Summary: Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.

Publication types

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

MeSH terms

  • Drug Discovery / methods
  • Gene Expression
  • Humans
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / drug therapy*
  • RNA, Messenger / metabolism*
  • Signal Transduction
  • Tomatine / analogs & derivatives*
  • Tomatine / therapeutic use
  • Triterpenes / therapeutic use*

Substances

  • Muscle Proteins
  • RNA, Messenger
  • Triterpenes
  • tomatidine
  • Tomatine
  • ursolic acid