Leucine attenuates muscle atrophy and autophagosome formation by activating PI3K/AKT/mTOR signaling pathway in rotator cuff tears

Cell Tissue Res. 2019 Oct;378(1):113-125. doi: 10.1007/s00441-019-03021-x. Epub 2019 Apr 24.


Rotator cuff tears (RCTs), the most common tendon injury, are always accompanied by muscle atrophy, which is characterized by excessive protein degradation. Autophagy-lysosome systems are the crucial proteolytic pathways and are activated in atrophying muscle. Thus, inhibition of the autophagy-lysosome pathway might be an alternative way to minimize skeletal muscle atrophy. In this present study, combined with a tendon transection-induced rat model of massive rotator cuff tears, HE staining and transmission electron microscopy methods, we found leucine supplementation effectively prevented muscle atrophy, muscle injury and autophagosome formation. Utilizing immunoblotting, we discovered that leucine supplementation is able to inhibit the rise in autophagy-related protein expression (including LC3, Atrogin-1, MuRF1, Bnip3 and FoxO3) driven by tendon transection. The PI3K/AKT/mTOR pathway that was essential in autophagosome formation and autophagy was blocked in atrophying muscle and reactivated in the presence of leucine. Once administrated with LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor), leucine mediated by the anti-atrophic effects was nearly blunted. These results suggest that leucine potentially attenuates tendon transection-induced muscle atrophy through autophagy inhibition via activating the PI3K/AKT/mTOR pathway.

Keywords: Autophagosome; Leucine; PI3K/AKT/mTOR pathway; Rotator cuff tears; Skeletal muscle atrophy.

MeSH terms

  • Animals
  • Autophagosomes / drug effects*
  • Autophagy-Related Proteins / metabolism
  • Leucine / pharmacology*
  • Leucine / therapeutic use
  • Male
  • Muscular Atrophy / drug therapy*
  • Muscular Atrophy / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Rotator Cuff Injuries / drug therapy*
  • Rotator Cuff Injuries / enzymology
  • Rotator Cuff Injuries / pathology
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*


  • Autophagy-Related Proteins
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Leucine