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LETTERS TO THE EDITOR
Most importantly, we stated in the Introduction, but apparently with insufficient clarity, that we aimed to explore the concept that limitations in fuel delivery account for the kinetics of O2 uptake at the onset of contractile activity (8, 11, 12). Specifically, we stated, "It is difficult to envision how a dynamically changing fuel availability could independently give rise to monoexponential Jo kinetics." We wish that even a minor fraction of Dr. Kemp's considerable insight and analysis would have been devoted to this issue. This notion, generally termed "metabolic inertia," has received a good deal of attention in the literature, albeit not by one of the thirty references in Dr. Kemp's letter. Metabolic inertia has even formed the basis of a proposed therapeutic intervention into human disease (2).
Dr. Kemp's presentation provides a clear and important reminder that, in vivo, pH is not constant during the transition from a low to a higher metabolic rate, because phosphocreatine (PCr) splitting is a net alkalinizing reaction, which is balanced or exceeded by acidifying reactions (1). Moreover, the in vivo temporal discrepancies in these acid/base responses can allow distinction among models of control of respiration that otherwise appear inseparable (1). Our incubations were conducted at a constant pH 7.0, a constant total adenylate pool of 5.0 mM, and ATP turnover rates simulating moderate exercise, i.e., within the near-linear region in all four of Dr. Kemp's graphs. In other words, we realize that our experimental conditions were not configured to discriminate between competing control models of oxidative phosphorylation. On the other hand, fuel availability can substantially alter the steady-state feedback relation between energy phosphate concentrations and mitochondrial O2 consumption or ATP production rates in vitro (3, 5, 7), in perfused heart (10, 13), in human muscle during prolonged exercise (9), and in McArdle's patients infused with glucose to augment carbohydrate delivery to working muscle (4). But it seemed to us unlikely that "metabolic inertia" could influence the energy phosphate:Jo relation during what appeared to be a monoexponential transient, and then promptly withdraw such influence upon attainment of the steady state. Our experiments and analysis were couched in the context of the Meyer electrical analog model (6) primarily because its elegance offered such intuitive accessibility. If, during the onset of moderate, nonacidotic exercise, PCr discharge was necessary and sufficient to account for the time course of the approach to steady state, then any lag in substrate availability was an unlikely contributing factor. We completed this analysis by clamping the energy state of the incubation at an intermediate value followed by stepwise additions of pyruvate. Our results provided no support for the metabolic inertia hypothesis, although this was not mentioned in Dr. Kemp's otherwise quite complete review of our work.
The second point we must mention is the footnote comment that "At this point, Glancy et al. also cite the near-linearity of [PCr] with 
GATP (23), but this is a consequence, not a cause, of ATP buffering." We are curious in what sense ATP buffering is causing this near linearity. The high equilibrium constant of the creatine kinase reaction reflects, of course, the large negative standard free energy when PCr hydrolysis is linked to ATP synthesis. Initiation of ATP hydrolysis from this linked energy phosphate pool will therefore advance PCr breakdown, effecting the resynthesis of ATP ("ATP buffering"). It seems to us that ATP hydrolysis (a fall in GATP) causes PCr to fall, which results in the resynthesis (buffering) of the ATP concentration.
In summary, our study tested the predictions of the Meyer electrical analog model in vitro at constant pH, contrasting it with the implications of metabolic inertia. It was not intended to discount alternative feedback models of oxidative phosphorylation, and this largely explains any perceived oversight of models not included in our discussion.
FOOTNOTES
Address for reprint requests and other correspondence: W. T. Willis, Department of Kinesiology, Arizona State University, Tempe, AZ 85287-0404 (e-mail: waynewillis{at}asu.edu)
REFERENCES
1. Barstow TJ, Buchthal SD, Zanconato S, Cooper DM. Changes in potential controllers of human skeletal muscle respiration during incremental calf exercise. J Appl Physiol 77: 2169–2176, 1994.
1a. Glancy B, Barstow T, Willis WT. Linear relation between time constant of oxygen uptake kinetics, total creatine, and mitochondrial content in vitro. Am J Physiol Cell Physiol 294: C79–C87, 2008.
2. Greenhaff PL, Campbell-O'Sullivan SP, Constantin-Teodosiu D, Poucher SM, Roberts PA, Timmons JA. Metabolic inertia in contracting skeletal muscle: a novel approach for pharmacological intervention in peripheral vascular disease. Br J Clin Pharmacol 57: 237–243, 2004.[CrossRef][Web of Science][Medline]
3. Koretsky AP, Balaban RS. Changes in pyridine nucleotide levels alter oxygen consumption and extra-mitochondrial phosphates in isolated mitochondria: a 31P-NMR and NAD(P)H fluorescence study. Biochim Biophys Acta 893: 398–408, 1987.[Medline]
4. Lewis SF, Haller RG, Cook JD, Nunnally RL. Muscle fatigue in McArdle's disease studied by 31P-NMR: effect of glucose infusion. J Appl Physiol 59: 1991–1994, 1985.
5. Messer JI, Jackman MR, Willis WT. Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. Am J Physiol Cell Physiol 286: C565–C572, 2004.
6. Meyer RA. A linear model of muscle respiration explains monoexponential phosphocreatine changes. Am J Physiol Cell Physiol 254: C548–C553, 1988.
7. Moreno-Sanchez R, Hogue BA, Hansford RG. Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation. Biochem J 268: 421–428, 1990.[Web of Science][Medline]
8. Roberts PA, Loxham SJ, Poucher SM, Constantin-Teodosiu D, Greenhaff PL. Acetyl-CoA provision and the acetyl group deficit at the onset of contraction in ischemic canine skeletal muscle. Am J Physiol Endocrine 288: E327–E334, 2005.[CrossRef]
9. Sahlin K, Katz A, Broberg S. Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise. Am J Physiol Cell Physiol 259: C834–C841, 1990.
10. Starnes JW, Wilson DF, Erecinska M. Substrate dependence of metabolic state and coronary flow in perfused rat heart. Am J Physiol Heart Circ Physiol 249: H799–H806, 1985.
11. Timmons JA, Gustafsson T, Sundberg CJ, Jansson E, Greenhaff PL. Muscle acetyl group availability is a major determinant of oxygen deficit in humans during submaximal exercise. Am J Physiol Endocrinol Metab 274: E377–E380, 1998.
12. Timmons JA, Poucher SM, Constantin-Teodosiu D, Worrall V, Macdonald IA, Greenhaff PL. Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia. J Clin Invest 97: 879–883, 1996.[Web of Science][Medline]
13. Zweier JL, Jacobus WE. Substrate-induced alterations of high energy phosphate metabolism and contractile function in the perfused heart. J Biol Chem 262: 8015–8021, 1987.
Wayne T. Willis1
Brian Glancy1
Thomas J. Barstow2
1Department of Kinesiology
Arizona State University
Tempe
Arizona; and 2Department of Kinesiology
Kansas State University
Manhattan
Kansas
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