Glycogen Content Regulates Peroxisome Proliferator Activated Receptor-partial derivative (PPAR-partial derivative) Activity in Rat Skeletal Muscle

Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial beta-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1 alpha (PGC-1 alpha) and the transcription factor/nuclear receptor PPAR-partial derivative. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1 alpha and PPAR-partial derivative function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-partial derivative activity via chromatin immunoprecipitation (ChIP) assays, AMPK alpha 1/alpha 2 kinase activity, and the localization of AMPK and PGC-1 alpha. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-alpha 2 activity (147%, p<0.05), nuclear AMPK-alpha 2 and PGC-1 alpha, but no difference in AMPK-alpha 1 activity compared to CON. In addition, PPAR-partial derivative binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-partial derivative activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-partial derivative and glycogen content/substrate availability. The present study is the first to examine PPAR-partial derivative activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-partial derivative and initiates AMPK translocation in skeletal muscle in response to exercise.