title: Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle.
abstract: The hypothesis was tested that the variation of in vivo glycolytic flux with contraction frequency in skeletal muscle can be qualitatively and quantitatively explained by calcium-calmodulin activation of phosphofructokinase (PFK-1). Ischemic rat tibialis anterior muscle was electrically stimulated at frequencies between 0 and 80 Hz to covary the ATP turnover rate and calcium concentration in the tissue. Estimates of in vivo glycolytic rates and cellular free energetic states were derived from dynamic changes in intramuscular pH and phosphocreatine content, respectively, determined by phosphorus magnetic resonance spectroscopy ((31)P-MRS). Computational modeling was applied to relate these empirical observations to understanding of the biochemistry of muscle glycolysis. Hereto, the kinetic model of PFK activity in a previously reported mathematical model of the glycolytic pathway (Vinnakota KC, Rusk J, Palmer L, Shankland E, Kushmerick MJ. J Physiol 588: 1961-1983, 2010) was adapted to contain a calcium-calmodulin binding sensitivity. The two main results were introduction of regulation of PFK-1 activity by binding of a calcium-calmodulin complex in combination with activation by increased concentrations of AMP and ADP was essential to qualitatively and quantitatively explain the experimental observations. Secondly, the model predicted that shutdown of glycolytic ATP production flux in muscle postexercise may lag behind deactivation of PFK-1 (timescales: 5-10 s vs. 100-200 ms, respectively) as a result of accumulation of glycolytic intermediates downstream of PFK during contractions.
authors.affiliation: Computational Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. J.P.J.Schmitz@tue.nl
authors.forename: J P J
authors.initials: JP
authors.lastname: Schmitz
authors.forename: W
authors.initials: W
authors.lastname: Groenendaal
authors.forename: B
authors.initials: B
authors.lastname: Wessels
authors.forename: R W
authors.initials: RW
authors.lastname: Wiseman
authors.forename: P A J
authors.initials: PA
authors.lastname: Hilbers
authors.forename: K
authors.initials: K
authors.lastname: Nicolay
authors.forename: J J
authors.initials: JJ
authors.lastname: Prompers
authors.forename: J A L
authors.initials: JA
authors.lastname: Jeneson
authors.forename: N A W
authors.initials: NA
authors.lastname: van Riel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D006019:Glycolysis / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D010725:Phosphocreatine / Q000032:analysis / Q000378:metabolism; D025203:Phosphofructokinase-1, Muscle Type / Q000737:chemistry / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002147:Calmodulin; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D025203:Phosphofructokinase-1, Muscle Type; D002118:Calcium