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LETTER TO THE EDITOR
Recent human isolated muscle fiber studies suggest that phosphocreatine (PCr) and creatine (Cr) concentrations play a role in the regulation of mitochondrial respiration rate. To determine whether similar regulatory mechanisms are present in vivo, this study examined the relationship between skeletal muscle mitochondrial respiration rate and end-exercise PCr, Cr, PCr-to-Cr ratio (PCr/Cr), ADP, and pH by using 31P-magnetic resonance spectroscopy in 16 men and women (36.9 ± 4.6 yr). The initial PCr resynthesis rate and time constant (Tc) were used as indicators of mitochondrial respiration after brief (10–12 s) and exhaustive (1–4 min) dynamic knee extension exercise performed in placebo and creatine-supplemented conditions. The results show that the initial PCr resynthesis rate has a strong relationship with end-exercise PCr, Cr, and PCr/Cr (r > 0.80, P < 0.001), a moderate relationship with end-exercise ADP (r = 0.77, P < 0.001), and no relationship with end-exercise pH (r = –0.14, P = 0.34). The PCr Tc was not as strongly related to PCr, Cr, PCr/Cr, and ADP (r < 0.77, P < 0.001–0.18) and was significantly influenced by end-exercise pH (r = –0.43, P < 0.01). These findings suggest that end-exercise PCr and Cr should be taken into consideration when PCr recovery kinetics is used as an indicator of mitochondrial respiration and that the initial PCr resynthesis rate is a more reliable indicator of mitochondrial respiration compared with the PCr Tc.
The following is the abstract of the article discussed in the subsequent letter:
To the Editor: Smith et al. (7) argue that 31P-magnetic resonance spectroscopy (MRS) studies of phosphocreatine (PCr) recovery in creatine (Cr)-loaded muscle reveal direct effects of PCr and Cr, in addition to ADP, on mitochondrial respiration, as described in vitro (8). However:
If they are correct to assume that resting [ADP] (brackets denote concentration) is unaffected by Cr loading (7), their data are compatible with a single initial PCr resynthesis rate (V)-vs.-[ADP] relationship (solid line, Fig. 1A), arguably the dominant mechanism matching mitochondrial ATP production to demand in exercising muscle (5).
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[PCr] (3) and invasive physiology is interesting (Fig. 1D). Furthermore, the regression fits Smith et al. (7) give for V vs. [ADP], [PCr] (Fig. 1, A and D), PCr/Cr, and [Cr] (not shown) cover a limited range, excluding rest, and have no generalizable significance. Simulation (Fig. 1B) suggests that direct effects of PCr/Cr on mitochondrial Km for ADP (8) might explain the sigmoidicity of V vs. [ADP] in vivo (5) across the full dynamic range.
However, Cr loading reduces resting PCr-to-total Cr ratio by 7% (mean of 7 biopsy studies of which Ref. 2 is typical), implying increased [ADP] and thus a different V-[ADP] relationship (dashed line, Fig. 1A). Effects of PCr/Cr on Km for ADP (8) cannot explain this, being independent of total Cr concentration. Effects of [PCr] on Km (8) might contribute, although the simulated fit (Fig. 1C) is imperfect.
Because V is never maximal in MRS experiments, extrapolation is required to estimate "mitochondrial capacity" (3, 6). The physiology is debated, but these results (7) do not prove that PCr and Cr must be allowed for as well as ADP.
REFERENCES
Dr. Kemp suggests that [ADP] may rise with Cr ingestion and that this may account for the increase in mitochondrial respiration rendering our [PCr] and [Cr]-vs.-mitochondrial respiration relationships epiphenomenal. Muscle biopsy results indicate that creatine ingestion does not change [ADP] during rest, exercise, or recovery (3). Because creatine ingestion may increase the Cr-to-PCr ratio and the calculated ADP, it could be argued that the blunted resynthesis rate we observed with increasing ADP is actually artifact caused by overestimation of ADP. However, if our ADP data are adjusted for possible influences of Cr ingestion, the same relationship persists. Furthermore, if the Cr-supplemented data are removed from the regression analyses, thereby eliminating the ADP issue, the same relationships exist between mitochondrial respiration and our metabolic variables.
Dr. Kemp used our mean values from rest, brief exercise, and exhaustive exercise to support his argument that ADP alone is the primary mechanism controlling mitochondrial respiration (Fig. 1A in Letter to the Editor). It is concerning that mean data and only three actual data points were used to determine a curve fit. Additionally, the data in Dr. Kemp’s Fig. 1A do not appear to agree with our published data. Figure 1A herein presents the actual association between our mean [ADP] results and the fit we originally presented as well as the [ADP] curve fit from previous work by Dr. Kemp (Ref. 1, Fig. 2a). The remarkably similar curvilinear fit from these independent experiments suggests that our metabolic relationships are, in fact, generalizable. Although we cannot totally discount that our PCr and Cr relationships may in part be epiphenomena, our PCr-to-Cr ratio vs. respiration rate relationship derived from in vivo magnetic resonance spectroscopy (MRS) agrees with the results from human isolated muscle fiber experiments in which [ADP] is tightly controlled (4), as shown by Fig. 1B herein.
The practical importance of our study is that it clearly shows that experiments estimating mitochondrial respiratory rate using 31P-MRS need to consider end-exercise [PCr] and [Cr]. Whether the associations between [PCr] or [Cr] with mitochondrial respiration rate are epiphenomenal or a result of direct interaction is practically irrelevant, because end-exercise PCr resynthesis is the parameter used to estimate mitochondrial respiration rate in MRS experiments. Our data clearly show that PCr resynthesis rate is significantly affected by the end-exercise [PCr].
We thank Dr. Kemp for his active interest in our work and the Journal of Applied Physiology for the opportunity to address Dr. Kemp’s intriguing questions. We hope our answers clarify any confusion regarding the outcomes and interpretation of our paper.
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Scott J. Montain
US Army Research Institute of Environmental Medicine
Natick, Massachusetts
e-mail: scott.montain{at}us.army.mil
This article has been cited by other articles:
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  G. Kemp Physiological implications of linear kinetics of mitochondrial respiration in vitro Am J Physiol Cell Physiol, September 1, 2008; 295(3): C844 - C846. [Full Text] [PDF]
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 G. Kemp Altered creatine dependence of muscle mitochondrial respiration in vitro: what are the likely effects in vivo? J Appl Physiol, December 1, 2006; 101(6): 1814 - 1815. [Full Text] [PDF]
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60 mM, very high for 31P-magnetic resonance spectroscopy, so to avoid argument V here is relative to control resting [PCr].