Higher activation of autophagy in skeletal muscle of mice during endurance exercise in the fasted state

Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E964-74. doi: 10.1152/ajpendo.00270.2013. Epub 2013 Aug 20.


Activation of autophagy in skeletal muscle has been reported in response to endurance exercise and food deprivation independently. The purpose of this study was to evaluate whether autophagy was more activated when both stimuli were combined, namely when endurance exercise was performed in a fasted rather than a fed state. Mice performed a low-intensity running exercise (10 m/min for 90min) in both dietary states after which the gastrocnemius muscles were removed. LC3b-II, a marker of autophagosome presence, increased in both conditions, but the increase was higher in the fasted state. Other protein markers of autophagy, like Gabarapl1-II and Atg12 conjugated form as well as mRNA of Lc3b, Gabarapl1, and p62/Sqstm1 were increased only when exercise was performed in a fasted state. The larger activation of autophagy by exercise in a fasted state was associated with a larger decrease in plasma insulin and phosphorylation of Akt(Ser473), Akt(Thr308), FoxO3a(Thr32), and ULK1(Ser757). AMPKα(Thr172), ULK1(Ser317), and ULK1(Ser555) remained unchanged in both conditions, whereas p38(Thr180/Tyr182) increased during exercise to a similar extent in the fasted and fed conditions. The marker of mitochondrial fission DRP1(Ser616) was increased by exercise independently of the nutritional status. Changes in mitophagy markers BNIP3 and Parkin suggest that mitophagy was increased during exercise in the fasted state. In conclusion, our results highlight a major implication of the insulin-Akt-mTOR pathway and its downstream targets FoxO3a and ULK1 in the larger activation of autophagy observed when exercise is performed in a fasted state compared with a fed state.

Keywords: ER stress; LC3b; fission; mitophagy; signaling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy*
  • Biomarkers / metabolism
  • Cytoplasmic Vesicles / metabolism
  • Dynamins / genetics
  • Dynamins / metabolism
  • Fasting*
  • Female
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondrial Dynamics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Motor Activity*
  • Muscle, Skeletal / metabolism*
  • Physical Endurance
  • RNA, Messenger / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction
  • Up-Regulation*


  • Adaptor Proteins, Signal Transducing
  • BNip3 protein, mouse
  • Biomarkers
  • Gabarapl1 protein, mouse
  • Heat-Shock Proteins
  • Map1lc3b protein, mouse
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Dnm1l protein, mouse
  • Dynamins