Phosphocreatine/inorganic Phosphate Ratio Research Articles

Abnormal skeletal muscle oxidative capacity after lung transplantation by 31P-MRS.

Although lung transplantation improves exercise capacity by removal of a ventilatory limitation, recipients' postoperative maximum oxygen uptake (VO2max) remains markedly abnormal. To determine if abnormal skeletal muscle oxidative capacity contributes to this impaired aerobic capacity, nine lung transplant recipients and eight healthy volunteers performed incremental quadriceps exercise to exhaustion with simultaneous measurements of pulmonary gas exchange, minute ventilation, blood lactate, and quadriceps muscle pH and phosphorylation potential by 31P-magnetic resonance spectroscopy (31P-MRS). Five to 38 mo after lung transplantation, peak VO2 was decreased compared with that of normal control subjects (6.7 +/- 0.4 versus 12.3 +/- 1.0 ml/min/kg, p < 0.001), even after accounting for differences in age and lean body weight. Neither ventilation, arterial O2 saturation nor mild anemia could account for the decrease in aerobic capacity. Quadriceps muscle intracellular pH (pH(i)) was more acidic at rest (7.07 +/- 0.01 versus 7.12 +/- 0.01 units, p < 0.05) and fell during exercise from baseline values at a lower metabolic rate (282 +/- 21 versus 577 +/- 52 ml/min, p < 0.001). Regressions for pH(i) versus VO2, phosphocreatine/inorganic phosphate ratio (PCr/Pi) versus VO2, and blood lactate versus pH(i) were not different. Among transplant recipients, the metabolic rate at which pH(i) fell correlated closely with VO2max (r = 0.87, p < 0.01). The persistent decrease in VO2max after lung transplantation may be related to abnormalities of skeletal muscle oxidative capacity.

Late‐onset mitochondrial myopathy

In the majority of patients with mitochondrial encephalomyopathies, signs and symptoms appear in the first three decades of life. Here we report on a group of 9 older patients (> 69 years old) with late-onset skeletal myopathy characterized by focal accumulations of deleted mitochondrial DNAs (mtDNAs) and altered muscle energy status, suggestive of a primary mitochondrial disease. The clinical phenotype was somewhat variable. However, all patients shared a common feature of insidious moderate proximal muscle weakness; some also showed fatigability and axial muscle weakness. In situ hybridization analysis demonstrated accumulations of messenger RNAs transcribed from deleted mtDNAs in a relatively large number of muscle fibers in the patient group. These fiber segments appeared as ragged red with the modified Gomori trichrome stain and hyperreactive with a modified succinate dehydrogenase stain. Most were negative for cytochrome c oxidase activity. On transverse sections their mean frequency was 0.69% (trichrome) and 1.97% (succinate dehydrogenase) significantly above control levels. Multiple mtDNA deletions were demonstrated by the polymerase chain reaction in both the patients and an age-matched control group, but not in younger control subjects. Phosphorus 13 magnetic resonance spectroscopy of resting muscle showed a decreased phosphocreatine-inorganic phosphate ratio in the patient group. The myopathy in this group of patients appears to result from mitochondrial dysfunction related to the clonal expansion of different mtDNA deletions in individual fiber segments. While the origin of the mtDNA mutations is not clear, the phenotype seems to represent an exaggerated form of what is observed in the normal aging process.

EFFECTS OF SODIUM BICARBONATE ON STRIATED MUSCLE METABOLISM AND INTRACELLULAR pH DURING ENDOTOXIC SHOCK

The effects of HCO3Na load on acid-base balance and muscle intracellular bioenergetics have been investigated using 31P-magnetic resonance spectroscopy in an experimental model of endotoxinic shock. Anesthetized, mechanically ventilated, and paralyzed rats (n = 16) were given an intravenous bolus of Escherichia coli lipopolysaccharide (15 mg/kg). When shock was established they were randomly assigned to receive either HCO3Na intravenously (2 mmol/kg in 2 min) or an equimolar saline injection. Lipopolysaccharide induced a significant decrease in the levels of mean arterial pressure (58 +/- 6 vs. 120 +/- 8 mmHg), arterial pH (7.20 +/- .03 vs. 7.35 +/- .01), intracellular pH (6.86 +/- .04 vs. 7.08 +/- .01), a marked hyperlactatemia (7 +/- 3 vs. 1.2 +/- .2 mmol/L) and a drop in the phosphocreatine-inorganic phosphate ratio. In the bicarbonate-loaded rats, mean arterial pressure further decreased whereas it remained unchanged in the saline group. Bicarbonate increased arterial pH and PaCO2 transiently. In the saline group, arterial pH decreased and PaCO2 remained stable. In both groups, intracellular pH and high energy phosphates had a similar evolution. In this model of septic shock, partial correction of arterial pH using HCO3Na did not reduce the metabolic cellular injury in skeletal muscle. Based on these results, HCO3Na may be of limited therapeutic value in severe septic metabolic acidosis.

Metabolic correlates of adenosine formation in stimulated guinea pig heart

Adenosine release into epicardial fluid and coronary effluent of isolated isovolumic guinea pig hearts was examined at baseline and after stimulation with norepinephrine (30 nM) during 31P-nuclear magnetic resonance spectroscopy to monitor myocardial metabolism. At baseline flow (9.6 +/- 0.3 ml.min-1.g-1), epicardial and venous adenosine concentrations were 154 +/- 40 and 17 +/- 5 nM, respectively. The phosphorylation potential (log[ATP]/[ADP][Pi]) and the phosphocreatine-inorganic phosphate ratio ([PCr]/[Pi]) were 5.26 +/- 0.04 and 8.5 +/- 0.7, respectively. Norepinephrine increased left ventricular pressure, heart rate, and myocardial O2 consumption rate by approximately 21, 70, and 45%, respectively, and increased epicardial and venous adenosine to 496 +/- 74 and 461 +/- 94 nM, respectively. Log-[ATP]/[ADP][Pi] and [PCr]/[Pi] declined to 4.57 +/- 0.06 and 1.9 +/- 0.3, respectively. Epicardial [AMP] increased from 54 +/- 13 to 123 +/- 24 nM. AMP was not detectable in the venous effluent. Coronary resistance correlated with epicardial and venous [adenosine] (r = 0.86 and 0.90). Epicardial and venous [adenosine] correlated with log[ATP]/[ADP][Pi], [PCr]/[Pi], and cytosolic [AMP]. Hence, interstitial adenosine is linked to cytosolic metabolism and may regulate coronary vascular resistance. Venous adenosine underestimates epicardial adenosine at baseline but more closely approximates epicardial adenosine during norepinephrine infusion.

Cerebral Energy Metabolism and Oxygen State during Hypoxia in Neonate and Adult Dogs

The relationship between a noninvasive determination of relative oxygen saturation of Hb circulating in brain tissue (StO2) and energy metabolism was investigated with respect to age [dogs in three age groups (0 to 6-d-old, 7- to 21-d-old, and adults)] and to severity of brain hypoxia using double beam spectroscopy of Hb deoxygenation and nuclear magnetic resonance spectroscopy of energy metabolism. The in vivo oxy-Hb dissociation was determined from the relationship between StO2 curve in the adult dog brain and sagittal sinus oxygen partial pressure during graded hypoxemia and found to be sigmoidal with an oxygen dissociation constant of 26.6 mm Hg. This agreed with an in vitro determination for oxygen dissociation constant of 28.2 mm Hg in adult dog red cells. The arterial oxygen pressure at which brain StO2 was reduced by 50% was shifted toward the right with increasing age (22.2, 33.8, and 40.8 mm Hg, respectively). This correlated with an in vitro oxygen dissociation constant of red cell Hb of 17.0, 22.3, and 28.2 mm Hg in the three age groups, respectively. The phosphocreatine-inorganic phosphate ratio (PCr/Pi) was used to relate changes in cellular energy metabolism during hypoxia with changes in StO2. There was no change in PCr/Pi when StO2 had decreased to 50% of the control value. However, when the brain StO2 had decreased to between 7 and 15%, a reduction of PCr/Pi to 50% of the normoxic value occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Localized 31P magnetic resonance spectroscopy of large pediatric brain tumors

Fourteen children aged 1 week to 16 years, with a variety of large or superficial brain tumors, underwent localized in vivo 31P magnetic resonance spectroscopy of their tumor. Quantitative spectral analysis was performed by measuring the area under individual peaks using a computer algorithm. In eight patients with histologically benign tumors the spectra were considered to be qualitatively indistinguishable from normal brain. The phosphocreatine/inorganic phosphate ratio (PCr/Pi) averaged 2.0. Five patients had histologically malignant tumors; qualitatively, four of these were considered to have abnormal spectra, showing a decrease in the PCr peak. The PCr/Pi ratio for this group averaged 0.85, which was significantly lower than that seen in the benign tumor group (p less than 0.05). No difference between the two groups was seen in adenosine triphosphate or phosphomonoesters. It is concluded that a specific metabolic "fingerprint" for childhood brain tumors may not exist, but that some malignant tumors show a pattern suggestive of ischemia.

USE OF P-31 NMR IN DIAGNOSIS AND THERAPY OF A FAMILIAL CARDIOMYOPATHY

An 8 mo old female with a familial congenital hypertrophic cardiomyopathy and cardiomegaly showed a chronic hyperchloremic acidosis, nonketotic fasting hypoglycemia, normal ketogenesis from medium chain triglycerides, but evidence of an abnormal redox state. Serum and muscle carnitine content were low normal, 5 mo carnitine therapy had failed to halt disease progression. Muscle carnitine transferase activity was elevated. To determine 1) if in vivo P-31 NMR spectroscopy could detect a metabolic abnormality in human myocardium, and 2) if P-31 NMR could be used to evaluate therapy designed to improve myocardial energy production, measurements were made using a TMR-32 Oxford Research Systems magnet (30 cm bore, 1.9 Tesla) with a 5 cm surface coil positioned over the sternum. This demonstrated an abnormally low phosphocreatine/inorganic phosphate ratio (PCr/Pi) compared to control (1.0±0.05 vs 2.0±0.3, R<0.01) . PCr/Pi remained low in the fasting state with or without administered MCT oil, but improved substantially following I.V. glucose or a carbohydrate enriched meal (PCr/Pi = 1.8±0.1, not different from control). We conclude that P-31 NMR can be used to evaluate the high energy phosphate profile of the human heart. Furthermore, when used in conjunction with dietary manipulations, it can be used to optimize therapeutic interventions, as shown in redox manipulations in another female who had skeletal muscle cytochrome-b deficiency. (Biophys. Jour., Feb. 1984 abstract)

Mitochondrial regulation of phosphocreatine/inorganic phosphate ratios in exercising human muscle: a gated 31P NMR study.

31P NMR is used to determine the relationship between work output in the exercising human forearm and the steady-state capability of oxidative phosphorylation as measured by the phosphocreatine/inorganic phosphate ratio (PCr/Pi). Exercise intensities (one contraction per 5 sec) permitting comfortable continuation of activity for greater than 1 hr produced PCr/Pi of about 1 for a subject of moderate training. Linear relationships between work rate per unit volume of muscle and the 5-min mean PCr/Pi were found for the subject's left and right arms. The protocol affords sensitive criteria of muscle performance in normal subjects and of biochemical or vascular disease in abnormal subjects. The Pi, PCr, and ATP levels found by 31P NMR represent the initial values in the cycle of contraction and relaxation which permit restitution of resting state 4 prior to the next contraction and the continuation of steady-state work performance.