31P magnetic resonance spectroscopy of the Sherpa heart: a phosphocreatine/adenosine triphosphate signature of metabolic defense against hypobaric hypoxia.
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Of all humans thus far studied, Sherpas are considered by many high-altitude biomedical scientists as most exquisitely adapted for life under continuous hypobaric hypoxia. However, little is known about how the heart is protected in hypoxia. Hypoxia defense mechanisms in the Sherpa heart were explored by in vivo, noninvasive 31P magnetic resonance spectroscopy. Six Sherpas were examined under two experimental conditions [normoxic (21% FiO2) and hypoxic (11% FiO2) and in two adaptational states--the acclimated state (on arrival at low-altitude study sites) and the deacclimating state (4 weeks of ongoing exposure to low altitude). Four lowland subjects were used for comparison. We found that the concentration ratios of phosphocreatine (PCr)/adenosine triphosphate (ATP) were maintained at steady-state normoxic values (0.96, SEM = 0.22) that were about half those found in normoxic lowlanders (1.76, SEM = 0.03) monitored the same way at the same time. These differences in heart energetic status between Sherpas and lowlanders compared under normoxic conditions remained highly significant (P < 0.02) even after 4 weeks of deacclimation at low altitudes. In Sherpas under acute hypoxia, the heart rate increased by 20 beats per min from resting values of about 70 beats per min, and the percent saturation of hemoglobin decreased to about 75%. However, these perturbations did not alter the PCr/ATP concentration ratios, which remained at about 50% of the values expected in healthy lowlanders. Because the creatine phosphokinase reaction functions close to equilibrium, these steady-state PCr/ATP ratios presumably coincided with about 3-fold higher free adenosine diphosphate (ADP) concentrations. Higher ADP concentrations (i.e., lower [PCr]/[ATP] ratios) were interpreted to correlate with the Km values for ADP-requiring kinases of glycolysis and to reflect elevated carbohydrate contributions to heart energy needs. This metabolic organization is postulated as advantageous in hypobaria because the ATP yield per O2 molecule is 25-60% higher with glucose than with free fatty acids (the usual fuels utilized in the human heart in postfasting conditions).Keywords:
Hypoxia
Adenosine triphosphate
Creatine kinase
Myocardial ATP utilization and resynthesis during hypoxia and reoxygenation were studied in vivo as a function of maturation. Graded hypoxia was performed in newborn (NB; 4-10 days old, n = 6) and mature sheep (MAT; 30-60 days old, n = 6). Time-resolved 31P-nuclear magnetic resonance was used to monitor myocardial phosphates throughout hypoxia and to monitor reoxygenation concomitant with rate of myocardial O2 consumption (MVO2) measurement. Oxygen delivery and MVO2 were constant in both groups throughout hypoxia, with substantial and similar increases in both parameters during reoxygenation. Hypoxic myocardial lactate release was similar in NB and MAT. Phosphocreatine (PCr), but not ATP, decreased in NB only during milder hypoxia. Rapid PCr and slower ATP depletion occurred with severe hypoxia, consistent with ATP utilization/synthesis imbalance. Depletion rates were higher in MAT. Creatine rephosphorylation rates, measures of mitochondrial function reported as percentage of predicted values, were similar. 34 +/- 12 in NB and 26 +/- 9% in mature lambs. In conclusion, 1) phosphorylation potential decreases in NB but not MAT in response to a decreasing oxygen gradient; 2) ATP utilization during hypoxia increases more in mature lambs; 3) anaerobic ATP production is not greater in NB; and 4) despite the greater energy imbalance imposed on MAT during hypoxia, mitochondrial function is similar to NB during reoxygenation.
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Phosphorus‒31 saturation‒transfer NMR spectroscopy provides an elegant means to study fluxes through the creatine kinase reaction in human skeletal muscle. To obtain reliable quantitative kinetic information, experimental imperfections, such as incomplete saturation and radiofrequency bleed over need to be addressed appropriately. In resting muscle, creatine kinase was near equilibrium both in normal controls and in a patient with impaired oxidative phosphorylation. Oral intake of high doses of creatine monohydrate for several days resulted in significantly increased concentrations of phosphocreatine but had no measurable effect on the phosphocreatine resynthesis rate in resting muscle.
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Found in all vertebrates, creatine kinase catalyzes the reversible reaction of creatine and ATP forming phosphocreatine and ADP. Phosphocreatine may be viewed as a reservoir of "high-energy phosphate" which is able to supply ATP, the primary energy source in bioenergetics, on demand. Consequently, creatine kinase plays a significant role in energy homeostasis of cells with intermittently high energy requirements. The enzyme is of clinical importance and its levels are routinely used as an indicator of myocardial and skeletal muscle disorders and for the diagnosis of acute myocardial infarction. First identified in 1928, the enzyme has undergone intensive investigation for over 75 years. There are four major isozymes, two cytosolic and two mitochondrial, which form dimers and octamers, respectively. Depending on the pH, the enzyme operates by a random or an ordered bimolecular mechanism, with the equilibrium lying towards phosphocreatine production. Evidence suggests that conversion of creatine to phosphocreatine occurs via the in-line transfer of a phosphoryl group from ATP. A recent X-ray structure of creatine kinase bound to a transition state analog complex confirmed many of the predictions based on kinetic, spectroscopic, and mutagenesis studies. This review summarizes and correlates the more significant mechanistic and structural studies on creatine kinase.
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Abstract Phosphorylated metabolites concentrations and creatine kinase kinetics are measured by 31 P NMR in solution and in isovolumic perfused rat hearts submitted to hypo‐ and hyperthermia as well as to acidosis (37°C). In the organ, temperature variation from 40 to 25°C induces an increase of phosphocreatine (PCr) stores, a decrease of P i and ADP concentrations, but does not affect the ATP pool. Creatine kinase forward flux ( V for ) is gradually reduced when the temperature is lowered both in vitro and in perfused heart. In normothermic and hypothermic conditions, a relationship is found between cardiac performance (rate pressure product, RPP), V for and ATP synthesis estimated through the myocardial oxygen consumption rate (MVO 2 ). At 40°C however, the RPP is reduced although both V for and MVO 2 increase. In vitro experiments show an optimum pH of 7.7 for the forward creatine kinase reaction. In perfused heart submitted to acidosis, a decrease of PCr concentration is observed, whereas ATP and ADP contents remain unchanged. Heart creatine kinase flux increased as in hyperthermia. These high fluxes are attributed to the coupling of the creatine kinase reaction with energy consuming or producing reactions: the increase of energy demand related to non‐contractile processes could explain the high MVO 2 and V for observed in those conditions.
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Abstract We developed a new dedicated measurement protocol for dynamic 31 P MRS analysis in contracting calf muscles of the mouse, using minimally invasive assessment of the contractile force combined with the acquisition of spectroscopic data gated to muscle contraction and determination of phosphocreatine (PCr) recovery rate and ATP contractile cost. This protocol was applied in a comparative study of six wild type (WT) mice and six mice deficient in cytosolic creatine kinase and adenylate kinase isoform 1 (MAK −/− mice) using 70 repeated tetanic contractions at two contractions per minute. Force levels during single contractions, and metabolite levels and tissue pH during resting conditions were similar in muscles of MAK −/− and WT mice. Strikingly, muscle relaxation after contraction was significantly delayed in MAK −/− mice, but during repeated contractions, the decrease in the force was similar in both mouse types. Gated data acquisition showed a negligible PCr breakdown in MAK −/− immediately after contraction, without a concomitant decrease in ATP or tissue pH. This protocol enabled the determination of rapid PCr changes that would otherwise go unnoticed due to intrinsic low signal‐to‐noise ratio (SNR) in mouse skeletal muscles combined with an assessment of the PCr recovery rate. Our results suggest that MAK −/− mice use alternative energy sources to maintain force during repeated contractions when PCr breakdown is reduced. Furthermore, the absence of large increases in adenosine diphosphate (ADP) or differences in force compared to WT mice in our low‐intensity protocol indicate that creatine kinase (CK) and adenylate kinase (AK) are especially important in facilitating energy metabolism during very high energy demands. Copyright © 2009 John Wiley & Sons, Ltd.
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