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LETTERS TO THE EDITOR
Novartis Institutes for Biomedical Research, Incorporated, Cambridge, Massachusetts
REPLY: In his letter, "The interpretation of abnormal 31P magnetic resonance saturation transfer measurements of Pi/ATP exchange in insulin-resistant skeletal muscle" (2), Dr. Graham J. Kemp asserts that resting muscle ATP turnover as measured by 31P saturation transfer (ST) may be overestimated compared with other techniques. It is true that this measurement may not solely address the F1F0-ATPase reaction, but it also reflects ATP generation involving the glyceraldehyde-3-phosphate dehydrogenase and 3-phosphoglycerate kinase reactions. The extent to which this cycling contributes to the overall ATP production, and whether insulin-resistant states may be able to interfere, still remains to be determined. Therefore, in absence of such data, we would like to emphasize that many of the techniques presented by Dr. Kemp also require caveats, inherently limiting their comparison with 31P ST measurements. For example, near-infrared spectroscopy relies on a surface-weighted measurement that may not adequately account for the contribution of skin, which is less vascularized than muscle in terms of blood flow and is more susceptible to temperature fluctuations. Also, Dr. Kemp's cited studies used near-infrared spectroscopy signal and phosphocreatine kinetics measured during acute ischemia, a condition obviously linked to decreased mitochondrial activity. We also refer here to a recent study by Karakelides et al. (1) that demonstrated that insulin deficiency and the related metabolic changes were associated with reduced muscle mitochondrial ATP production measured using well-validated in vitro methodologies. Absolute values displayed in this article varied depending on substrate but incorporated a range, in good agreement with our findings: ATP production rate is 
3–10 µmol·min–1·g–1 in human (1) compared with 7–15 µmol·min–1·g–1 in rats (3). These changes, along with a reduced expression of oxidative phosphorylation genes, were observed despite an increase in whole body oxygen consumption. In a more biological context, we utilized a diet-induced obese rat model of uncontrolled insulin resistance to show decreased ATP turnover relative to age-matched chow-fed controls, and Karakiledes et al. presented a decline in mitochondrial ATP production when patients with well-controlled type 1 diabetes were deprived of their normal regimen of long-acting insulin. Although insulin resistance and insulin deficiency are not the same, both models demonstrated similar effects.
As for the species differences noted, although ATP turnover may generally scale with weight, it is possible that the contribution of skeletal muscle to basal metabolism is limited compared with other organs such as the liver and brown fat tissue, the implications of brown fat in thermogenesis being well recognized.
Dr. Kemp also raises concerns as to whether a decrease in ATP turnover may be used as a marker of mitochondrial dysfunction instead of a simple reflection of the overall ATP demand. Rightfully, ADP most likely controls the rate of mitochondrial ATP synthesis under low-intensity exercise conditions (7). However, as Dr. Kemp points out (2), there is no indication in the literature that the same applies in resting muscle. In fact, our data obtained from muscles at rest demonstrate that, although rats were fed a fat-enriched diet for 2 mo, leading to insulin resistance, neither Pi nor ADP concentrations were different from those measured in rats on a normal chow diet (Table 1). Therefore, it is fair to assume that the free energy of ATP hydrolysis (
GATP) remained unchanged (at least under basal metabolism conditions), supporting the notion (6) that the decrease in ATP synthesis observed in rats fed a fat-enriched diet resulted primarily from mitochondrial loss or impairment. Unfortunately, we are not aware of a study that analyzes the specific effects of long-term high-fat feeding on O2 utilization per se. If such data could show unchanged or even increased oxidative metabolism in skeletal muscle in response to high-fat exposure, then a decrease in muscle ATP synthesis rate would certainly suggest a fat-mediated mitochondrial defect. A related phenomenon may also be observable in humans. Lean offsprings of type 2 diabetes patients display an 30% reduction in the ATP synthase rate, a sign of an inherited mitochondrial defect, according to a recently published paper by Petersen et. al. (5). Since these subjects presumably have a basal metabolic rate similar to age- and body weight-matched control subjects, one can safely hypothesize that their overall ATP demand is alike as well. Thus, the relative contribution of nonoxidative pathways to the overall ATP production may in fact be greater. Most importantly, these in vivo NMR data provided clear indication of an abnormal mitochondrial function in offspring of type 2 diabetes mellitus patients that has subsequently been supported with evidence (4) for reduced mitochondrial density in these same patients.
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FOOTNOTES
Address for reprint requests and other correspondence: D. Laurent, Novartis Institutes for Biomedical Research, Inc., 250 Mass Ave., Cambridge, MA 02139 (e-mail: didier.laurent{at}novartis.com)
REFERENCES
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