Lactate Contributes to Glyceroneogenesis and Glyconeogenesis in Skeletal Muscle by Reversal of Pyruvate Kinase

J Biol Chem. 2015 Dec 18;290(51):30486-97. doi: 10.1074/jbc.M115.689174. Epub 2015 Oct 21.


Phosphoenolpyruvate (PEP) generated from pyruvate is required for de novo synthesis of glycerol and glycogen in skeletal muscle. One possible pathway involves synthesis of PEP from the citric acid cycle intermediates via PEP carboxykinase, whereas another could involve reversal of pyruvate kinase (PK). Earlier studies have reported that reverse flux through PK can contribute carbon precursors for glycogen synthesis in muscle, but the physiological importance of this pathway remains uncertain especially in the setting of high plasma glucose. In addition, although PEP is a common intermediate for both glyconeogenesis and glyceroneogenesis, the importance of reverse PK in de novo glycerol synthesis has not been examined. Here we studied the contribution of reverse PK to synthesis of glycogen and the glycerol moiety of acylglycerols in skeletal muscle of animals with high plasma glucose. Rats received a single intraperitoneal bolus of glucose, glycerol, and lactate under a fed or fasted state. Only one of the three substrates was (13)C-labeled in each experiment. After 3 h of normal awake activity, the animals were sacrificed, and the contribution from each substrate to glycogen and the glycerol moiety of acylglycerols was evaluated. The fraction of (13)C labeling in glycogen and the glycerol moiety exceeded the possible contribution from either plasma glucose or muscle oxaloacetate. The reverse PK served as a common route for both glyconeogenesis and glyceroneogenesis in the skeletal muscle of rats with high plasma glucose. The activity of pyruvate carboxylase was low in muscle, and no PEP carboxykinase activity was detected.

Keywords: citric acid cycle; glycerol; glycobiology; glycogen synthase; phosphoenolpyruvate carboxykinase; pyruvate carboxylase (PC); pyruvate dehydrogenase complex (PDC); pyruvate kinase; skeletal muscle metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Gluconeogenesis / drug effects*
  • Glycerol / metabolism*
  • Lactic Acid / pharmacology*
  • Male
  • Muscle, Skeletal / metabolism*
  • Phosphoenolpyruvate / metabolism
  • Pyruvate Kinase / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Blood Glucose
  • Lactic Acid
  • Phosphoenolpyruvate
  • Pyruvate Kinase
  • Glycerol