Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle

J. P. J. Schmitz*, W. Groenendaal, B. Wessels, R. W. Wiseman, P. A. J. Hilbers, K. Nicolay, J. J. Prompers, J. A. L. Jeneson, N. A. W. van Riel

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    19 Citaten (Scopus)

    Samenvatting

    Schmitz JP, Groenendaal W, Wessels B, Wiseman RW, Hilbers PA, Nicolay K, Prompers JJ, Jeneson JA, van Riel NA. Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle. Am J Physiol Cell Physiol 304: C180-C193, 2013. First published October 31, 2012; doi:10.1152/ajpcell.00101.2012.-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 (P-31-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.

    Originele taal-2English
    Pagina's (van-tot)C180-C193
    Aantal pagina's14
    TijdschriftAmerican journal of physiology-Cell physiology
    Volume304
    Nummer van het tijdschrift2
    DOI's
    StatusPublished - jan.-2013

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