A metabolic control analysis of kinetic controls in ATP free energy metabolism in contracting skeletal muscle

J. A. L. Jeneson, H. V. Westerhoff, M. J. Kushmerick
2000 American Journal of Physiology - Cell Physiology  
Jeneson, J. A. L., H. V. Westerhoff, and M. J. Kushmerick. A metabolic control analysis of kinetic controls in ATP free energy metabolism in contracting skeletal muscle. Am J Physiol Cell Physiol 279: C813-C832, 2000.-A system analysis of ATP free energy metabolism in skeletal muscle was made using the principles of metabolic control theory. We developed a network model of ATP free energy metabolism in muscle consisting of actomyosin ATPase, sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase, and
more » ... ndria. These components were sufficient to capture the major aspects of the regulation of the cytosolic ATP-to-ADP concentration ratio (ATP/ADP) in muscle contraction and had inherent homeostatic properties regulating this free energy potential. As input for the analysis, we used ATP metabolic flux and the cytosolic ATP/ADP at steady state at six contraction frequencies between 0 and 2 Hz measured in human forearm flexor muscle by 31 P-NMR spectroscopy. We used the mathematical formalism of metabolic control theory to analyze the distribution of fractional kinetic control of ATPase flux and the ATP/ADP in the network at steady state among the components over this experimental range and an extrapolated range of stimulation frequencies (up to 10 Hz). The control analysis showed that the contractile actomyosin ATPase has dominant kinetic control of ATP flux in forearm flexor muscle over the 0-to 1.6-Hz range of contraction frequencies that resulted in steady states, as determined by 31 P-NMR. However, flux control begins to shift toward mitochondria at Ͼ1 Hz. This inversion of flux control from ATP demand to ATP supply control hierarchy progressed as the contraction frequency increased past 2 Hz and was nearly complete at 10 Hz. The functional significance of this result is that, at steady state, ATP free energy consumption cannot outstrip the ATP free energy supply. Therefore, this reduced, three-component muscle ATPase system is inherently homeostatic. cellular energetics; skeletal muscle; metabolic control analysis A NUMBER OF APPROACHES have been developed to describe muscle energetics, starting with Hill's analysis of heat and mechanics. Present analyses of muscle energetics obtained by noninvasive 31 P-NMR measurements can be expressed as specific biochemical mech-Address for reprint requests and other correspondence: J. A. L. Downloaded from where the Hill coefficient (n H ) is 2 for SR ATPase and 3 for AM ATPase (44) . [Ca 2ϩ ] required for half-maximal stimulation ([Ca 2ϩ ] 50 ) is ϳ0.2 M for SR ATPase and ϳ0.8 M for AM ATPase (44). In the unstimulated muscle cell, cytosolic C814 Downloaded from Ϫ ln͕1 ϩ [KЈ 50 /(v 3 ⅐ ⌬t)] 3 ͖ ] Under the limit condition ⌬t30, i.e., at high contraction frequencies, the term [KЈ 50 /(v 3 ⌬t)] 3 Ͼ 1. Also, K 50 , ␤, and n P Ca C818 CONTROL ANALYSIS OF ATP FREE ENERGY METABOLISM IN MUSCLE by on August 9, 2017 http://ajpcell.physiology.org/ Downloaded from 2Ј was calculated using Eq. 13. Steady-state ATP/ADP at these stimulation frequencies were extrapolated from the measured relation between stimulation frequency and ATP/ADP (Fig. 3C) . J
doi:10.1152/ajpcell.2000.279.3.c813 pmid:10942732 fatcat:jte2xvcyf5bdjfdnyfcw2abw7e