Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles.

Magnetic resonance spectroscopy-based magnetization transfer techniques (MT) are commonly used to assess the rate of oxidative (i.e., mitochondrial) ATP synthesis in intact tissues. Physiologically appropriate interpretation of MT rate data depends on accurate appraisal of the biochemical events that contribute to a specific MT rate measurement. The relative contributions of the specific enzymatic reactions that can contribute to a MT P(i)→ATP rate measurement are tissue dependent; nonrecognition of this fact can bias the interpretation of MT P(i)→ATP rate data. The complexities of MT-based measurements of mitochondrial ATP synthesis rates made in striated muscle and other tissues are reviewed, following which, the adverse impacts of erroneous P(i)→ATP rate data analyses on the physiological inferences presented in selected published studies of cardiac and skeletal muscle are considered.

[1]  B. Saltin,et al.  Human muscle blood flow and metabolism studied in the isolated quadriceps muscles. , 1998, Medicine and science in sports and exercise.

[2]  K. Sahlin,et al.  Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes , 2007, Diabetes.

[3]  A. From,et al.  31P NMR measurement of mitochondrial uncoupling in isolated rat hearts. , 1990, The Journal of biological chemistry.

[4]  S Nioka,et al.  Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. Radda,et al.  31P-NMR saturation transfer measurements of exchange between Pi and ATP in the reactions catalysed by glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase in vitro. , 1987, Biochimica et biophysica acta.

[6]  K. Uğurbil,et al.  Saturation-transfer studies of ATP-Pi exchange in isolated perfused rat liver. , 1987, Biochimica et biophysica acta.

[7]  M. Portman.  Measurement of unidirectional P(i)-->ATP flux in lamb myocardium in vivo. , 1994, Biochimica et biophysica acta.

[8]  J R Neely,et al.  Control of Maximum Rates of Glycolysis in Rat Cardiac Muscle , 1979, Circulation research.

[9]  A. From,et al.  31P NMR studies of ATP synthesis and hydrolysis kinetics in the intact myocardium. , 1987, Biochemistry.

[10]  K. Petersen,et al.  Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals , 2008, Proceedings of the National Academy of Sciences.

[11]  R. Shulman,et al.  31P NMR saturation-transfer measurements in Saccharomyces cerevisiae: characterization of phosphate exchange reactions by iodoacetate and antimycin A inhibition. , 1987, Biochemistry.

[12]  R. Balaban,et al.  Succinyl-CoA synthetase is a phosphate target for the activation of mitochondrial metabolism. , 2009, Biochemistry.

[13]  K. Petersen,et al.  Effect of triiodothyronine on mitochondrial energy coupling in human skeletal muscle. , 2001, The Journal of clinical investigation.

[14]  J. Schrader,et al.  Spatial heterogeneity of energy turnover in the heart , 2001, Pflügers Archiv.

[15]  Y. Asmann,et al.  Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association With Severe Insulin Resistance , 2008, Diabetes.

[16]  G. Kemp.  The interpretation of abnormal 31P magnetic resonance saturation transfer measurements of Pi/ATP exchange in insulin-resistant skeletal muscle. , 2008, American journal of physiology. Endocrinology and metabolism.

[17]  K. Petersen,et al.  Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents , 2005, PLoS medicine.

[18]  A. From,et al.  31P NMR Studies of the Kinetics and Regulation of Oxidative Phosphorylation in the Intact Myocardium a , 1987, Annals of the New York Academy of Sciences.

[19]  Jiaping Gao,et al.  Insulin-stimulated mitochondrial adenosine triphosphate synthesis is blunted in skeletal muscles of high-fat-fed rats. , 2008, Metabolism: clinical and experimental.

[20]  Wei Chen,et al.  Measurement of unidirectional Pi to ATP flux in human visual cortex at 7 T by using in vivo 31P magnetic resonance spectroscopy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. From,et al.  31P NMR measurement of ATP synthesis rate in perfused intact rat hearts , 1986, FEBS letters.

[22]  Wei Chen,et al.  Efficient in vivo 31P magnetization transfer approach for noninvasively determining multiple kinetic parameters and metabolic fluxes of ATP metabolism in the human brain , 2007, Magnetic Resonance in Medicine.

[23]  J. Górski,et al.  Oxygen cost of twitch and tetanic isometric contractions of rat skeletal muscle. , 1986, The American journal of physiology.

[24]  R. Liao,et al.  Increased Glucose Uptake and Oxidation in Mouse Hearts Prevent High Fatty Acid Oxidation but Cause Cardiac Dysfunction in Diet-Induced Obesity , 2009, Circulation.

[25]  I. Kettelhut,et al.  Glyconeogenic pathway in isolated skeletal muscles of rats. , 2002, Canadian journal of physiology and pharmacology.

[26]  A. From,et al.  ATP synthesis kinetics and mitochondrial function in the postischemic myocardium as studied by 31P NMR. , 1988, The Journal of biological chemistry.

[27]  S. Dufour,et al.  Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Erecińska,et al.  Homeostatic regulation of cellular energy metabolism: experimental characterization in vivo and fit to a model. , 1978, The American journal of physiology.

[29]  K. Nicolay,et al.  Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  K. Petersen,et al.  Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. , 2005, The Journal of clinical investigation.

[31]  A. From,et al.  Regulation of the oxidative phosphorylation rate in the intact cell. , 1990, Biochemistry.

[32]  G. Radda,et al.  Kinetic control of mitochondrial ATP synthesis. , 1986, Biochemistry.

[33]  K. Petersen,et al.  Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients , 2007, Diabetes.

[34]  J. Holloszy.  Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance. , 2009, The American journal of clinical nutrition.

[35]  N. M. van den Broek,et al.  Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction. , 2008, European journal of endocrinology.

[36]  R S Balaban,et al.  Interpretation of ³¹P NMR saturation transfer experiments: what you can't see might confuse you. Focus on "Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles". , 2011, American journal of physiology. Cell physiology.

[37]  E Moser,et al.  Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment , 2008, NMR in biomedicine.

[38]  Peter Nowotny,et al.  Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes , 2007, PLoS medicine.

[39]  K. Petersen,et al.  Disordered lipid metabolism and the pathogenesis of insulin resistance. , 2007, Physiological reviews.

[40]  A. From,et al.  Measurement of ATP synthesis rates by 31P‐NMR spectroscopy in the intact myocardium in vivo , 1990, Magnetic resonance in medicine.

[41]  S. Dufour,et al.  13C/31P NMR Assessment of Mitochondrial Energy Coupling in Skeletal Muscle of Awake Fed and Fasted Rats , 2000, The Journal of Biological Chemistry.

[42]  J. Knuuti,et al.  Relationship between muscle blood flow and oxygen uptake during exercise in endurance-trained and untrained men. , 2005, Journal of applied physiology.

[43]  J. Ingwall,et al.  Endogenous nitric oxide enhances coupling between O2 consumption and ATP synthesis in guinea pig hearts. , 2001, American journal of physiology. Heart and circulatory physiology.

[44]  G. Radda,et al.  31P NMR magnetization-transfer measurements of ATP turnover during steady-state isometric muscle contraction in the rat hind limb in vivo. , 1989, Biochemistry.

[45]  Pierre J Magistretti,et al.  Neuroenergetics: Calling Upon Astrocytes to Satisfy Hungry Neurons , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[46]  J. Roca,et al.  Evidence of O2 supply-dependent VO2 max in the exercise-trained human quadriceps. , 1999, Journal of applied physiology.