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G J Kemp

Publications and source records attributed to G J Kemp.

At least 73 records · Page 4Linked to original sources
PubMed1995

ATP production and mechanical work in exercising skeletal muscle: a theoretical analysis applied to 31P magnetic resonance spectroscopic studies of dialyzed uremic patients.

31P magnetic resonance spectroscopy (31P MRS) can yield much information about bioenergetics in skeletal muscle. During mixed aerobic/glycolytic exercise, changes in phosphocreatine (PCr) concentration and pH may be abnormal because of reduced muscle mass or reduced efficiency (which the authors combine here as "effective muscle mass") or because of reduced oxidative capacity. The authors show how these can be distinguished by calculating the nonoxidative and oxidative costs of mechanical work, and also of work per unit of effective muscle mass (measured using the initial rate of ATP turnover). These quantities are substantially time-independent during incremental exercise, and so can be used to compare exercise studies of differing duration. The authors illustrate this analysis by showing that in dialyzed patients with chronic renal failure, the substantial exercise abnormalities seen by 31P MRS are due mainly to a decrease in effective muscle mass, which outweighs the oxidative defect implied by the abnormal PCr recovery kinetics.

Adenosine Triphosphate↗
PubMed1995

A relationship between impaired fetal growth and reduced muscle glycolysis revealed by 31P magnetic resonance spectroscopy.

Thinness at birth is associated with insulin resistance and an increased prevalence of non-insulin-dependent diabetes mellitus in adult life. As muscle is an important site of insulin resistance, and because thin babies have reduced muscle mass, thinness at birth may affect muscle structure and function and impair carbohydrate metabolism. We have therefore used 31P magnetic resonance spectroscopy to investigate the bioenergetics of gastrocnemius and flexor digitorum superficialis muscles in 16 normoglycaemic women who had a low ( < or = 23 kg/m3) and 9 women who had a high (> 23 kg/m3) ponderal index at birth. In the flexor digitorum superficialis study anaerobic metabolism was stressed with a constant heavy workload. Low ponderal index subjects fatigued more rapidly (3.3 vs 5.8 min); as phosphocreatine decreased, the accompanying drop in muscle pH was less than in the high ponderal index group. In the first minute of exercise phosphocreatine fell and adenosine diphosphate rose more rapidly (p=0.04 and 0.03, respectively). Gastrocnemius showed a similar trend late in exercise (this exercise was more oxidative, becoming more anaerobic with increasing workload). These changes were not explained by differences in body composition, muscle mass or blood flow. The findings are consistent with a decreased lactic acid and glycolytic adenosine triphosphate production in the low ponderal index group and suggest the possibility that the mechanisms which control substrate utilisation and metabolism in adult life be programmed during prenatal life.

Adenosine Diphosphate↗
PubMed1995

Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study.

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

Adenosine Triphosphate↗
PubMed1995

Calf muscle mitochondrial and glycogenolytic ATP synthesis in patients with claudication due to peripheral vascular disease analysed using 31P magnetic resonance spectroscopy.

1. We set out to define abnormalities of oxidative ATP synthesis, cellular proton efflux and the efficiency of ATP usage in gastrocnemius muscle of patients with claudication due to peripheral vascular disease, using data obtained by 31P magnetic resonance spectroscopy during aerobic exercise and recovery. 2. Eleven patients with moderate claudication were studied and results were compared with 25 age-matched control subjects. Changes in pH and phosphocreatine concentration during recovery were used to calculate the maximum rate of oxidative ATP synthesis (Qmax.) and the capacity of net proton efflux. Changes in pH and phosphocreatine concentration were used to estimate rates of non-oxidative and (indirectly) oxidative ATP synthesis throughout exercise, taking account of abnormalities in proton efflux during exercise. 3. In patients with claudication, slow post-exercise phosphocreatine recovery showed a 42 +/- 9% decrease in Qmax., and the slow ADP recovery was consistent with this. pH recovery was slow, showing a 77 +/- 9% decrease in the capacity for proton efflux. Both abnormalities are compatible with a substantial reduction in muscle blood flow. 4. During exercise, increased phosphocreatine depletion and intracellular acidification were a consequence of impaired oxidative ATP synthesis and the consequent increase in non-oxidative ATP synthesis, compounded by reduced proton efflux. The acidification prevented an increase in ADP concentration which could otherwise partially compensate for the oxidative defect. All these abnormalities are compatible with a reduced muscle blood flow. 5. In addition, initial-exercise changes in pH and phosphocreatine concentration implied a 44 +/- 5% reduction in 'effective muscle mass', necessitating an ATP turnover (per litre of muscle water) twice as high for given power output as in control muscle. Some of this is probably due to a localized loss of muscle fibres, but the rest appears to reflect reduced metabolic efficiency of the muscle. This is not a direct consequence of reduced blood flow, and may be related to change in muscle fibre type.

Adenosine Triphosphate↗
PubMed1995

Skeletal muscle mitochondrial function studied by kinetic analysis of postexercise phosphocreatine resynthesis.

To investigate mitochondrial regulation and its response to a defect in oxidative metabolism, we used 31P-magnetic resonance spectroscopy to study phosphocreatine (PCr) recovery in rat leg muscle after sciatic nerve stimulation at 1-4 Hz. We studied normal animals and animals with defective skeletal muscle mitochondrial function after experimental cardiac infarction. To analyze these data, we used three current theoretical approaches to the control of mitochondrial ATP synthesis, based on its hyperbolic relationship to cytosolic ADP concentration and on its linear relationships to PCr concentration and the free energy of ATP hydrolysis. The mitochondrial ADP concentration for one-half maximum rate of ATP synthesis appeared at least twice as high as the 30 microM expected from in vitro studies. According to all three approaches, the apparent maximum rate of ATP synthesis was independent of stimulation frequency and end-exercise pH and PCr and ADP concentrations and was reduced by approximately 50% after experimental cardiac infarction. Analysis of PCr recovery kinetics is a robust and practical way to study mitochondrial regulation and to quantify effective mitochondrial defects in vivo.

Adenosine Diphosphate↗
PubMed1995

Triiodothyronine-induced changes in proton efflux from rat skeletal muscle in vivo.

Hyperthyroidism is associated with muscle weakness, abnormal aerobic metabolism and increased lactate production. Muscle cell acidification during exercise is reduced, suggesting abnormally increased proton efflux. Using 31P magnetic resonance spectroscopy to measure cell pH and phosphocreatine concentration, we quantified effective proton efflux from rat leg muscle in vivo following 10-Hz sciatic nerve stimulation in seven rats injected with triiodothyronine (T3) for 5 days and in 11 controls. Proton efflux during recovery was sigmoidally pH-dependent in both groups but the initial proton efflux rate did not differ (16 +/- 3 mmol.kg-1.min-1 in treated animals vs 15 +/- mmol.kg-1.min.-1 in controls), despite significantly smaller pH change from basal in treated animals (0.60 +/- 0.04 vs 0.78 +/- 0.03 in controls, p = 0.002). The pH dependence of proton efflux can be characterized by an apparent Km, defined as the pH below basal at which proton efflux rate falls to half its start-of-recovery value. This Km was smaller in the T3-treated group (0.44 +/- 0.04 vs 0.59 +/- 0.03 in controls, p = 0.02). This suggests an increased affinity for protons by cell membrane proton transport processes such as the sodium-proton antiporter and may explain some of the metabolic changes seen clinically in hyperthyroid skeletal muscle.

Animals↗
PubMed1995

Abnormal ATP turnover in rat leg muscle during exercise and recovery following myocardial infarction.

OBJECTIVE: Clinical and animal studies show increased acidification of skeletal muscle during exercise in heart failure, implying increased anaerobic metabolism, and impaired recovery from exercise, implying defective oxidative function. This study aimed to define the quantitative relationship between these changes in exercise and recovery and relate skeletal muscle bioenergetics to cardiovascular function. METHODS: Wistar rats were studied four weeks after myocardial infarction or a sham operation. 31P magnetic resonance spectroscopy of the hind leg muscle was used to estimate rates of oxidative and non-oxidative ATP synthesis from changes in pH and phosphocreatine concentration during sciatic nerve stimulation and to estimate the maximum rate of mitochondrial ATP synthesis from the kinetics of phosphocreatine recovery after stimulation. RESULTS: Following myocardial infarction, cardiac function was abnormal, with evidence of left ventricular hypertrophy, failure, and diminished arterial pressure. There was impaired phosphocreatine recovery, suggesting an approximate halving of the maximum rate of mitochondrial ATP synthesis. CONCLUSIONS: The response to exercise of the infarct group was abnormal and was quantitatively consistent with the reduced maximum rate of mitochondrial ATP synthesis inferred from recovery, the oxidative deficit during exercise being made up by increased glycogenolysis, causing sufficient acidification to prevent an appropriate increase in [ADP].

Adenosine Triphosphate↗
PubMed1994

Bioenergetics of skeletal muscle in mitochondrial myopathy.

31Phosphorus nuclear magnetic resonance spectroscopy was used to examine skeletal muscle in 29 patients with mitochondrial myopathy, 9 male and 20 female. Gastrocnemius was investigated in 15 patients and 30 normal subjects and finger flexor muscle (flexor digitorum superficialis, fds) in 24 patients and 35 normal controls. Both muscles were studied in 10 of the patients. Results were abnormal (outside the full range of normal values) in all but 2 patients. In 86% of patients (25/29) abnormalities were detected in resting muscle. In most cases there was a low phosphocreatine/ATP ratio, high calculated free [ADP] and low phosphorylation potential. At rest, abnormality was detected with equal ease in fds and gastrocnemius. Exercise and recovery increased the sensitivity of MRS in detecting abnormal metabolism. Finger flexion was better tolerated by patients than plantar flexion and gave bigger changes in metabolite concentrations and intracellular pH. Thus, results from fds were more easily differentiated from normal. Exercise duration was significantly shorter than in controls while phosphocreatine depletion was more rapid than normal, consistent with a shortfall in mitochondrial ATP synthesis. Nearly all patients (25/27, 93%) showed abnormalities during recovery from exercise. [ADP] was high during exercise and its recovery was delayed, providing increased drive for oxidative phosphorylation. Phosphocreatine resynthesis during recovery (which reflects oxidative ATP synthesis) was slow both in absolute terms and in relation to [ADP]. Recovery of intracellular pH after exercise was significantly more rapid than normal, consistent with an upregulation of proton efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Interactions of mitochondrial ATP synthesis and the creatine kinase equilibrium in skeletal muscle.

In skeletal muscle, creatine kinase imposes constraints on the concentrations of phosphocreatine, creatine, ATP and ADP, which complicate our understanding of the regulation of mitochondrial ATP synthesis, because correlations between oxidation rate (Q) and metabolite concentrations cannot prove causal relations. Two kinds of theory of mitochondrial control in vivo have evolved, based on (i) the hyperbolic relationship between Q and cytosolic [ADP] and (ii) linear correlations between Q and, for example, free energy of ATP hydrolysis. This paper examines some relationships between these theories in order to show (i) to what extent they may be regarded as different expressions of the same metabolic mechanisms, (ii) how they can be understood in terms of general principles of feedback control, and (iii) how they explain relationships between mitochondrial function and resting metabolite concentrations.

Adenosine Triphosphate↗
PubMed1994

Modulation of Pi transport in skeletal muscle by insulin and IGF-1.

In vivo, skeletal muscle Pi uptake influences both muscle cellular [Pi] and plasma [Pi], and may mediate the hypophosphataemic effects of insulin and insulin-like growth factor 1 (IGF-1). These effects were investigated in the cultured mouse myoblast cell line G8 and the isolated incubated rat soleus. The low Km for Pi in G8 cells is consistent with in vivo evidence that muscle cell [Pi] is partially protected against changes in plasma [Pi]. Insulin and IGF-1 stimulated Na-dependent Pi influx: in G8 cells both increased Vmax, with no change in Km, but while the insulin response occurred within 15 min and rapidly reversed upon insulin withdrawal, the response to IGF-1 occurred only after 60 min and persisted at least 60 min following IGF-1 withdrawal. Furthermore, only the IGF-1 response was inhibited by cycloheximide. We suggest that IGF-1 operates through de novo protein synthesis, while insulin stimulates transporter recruitment to the cell surface.

Animals↗
PubMed1994

pH control in rat skeletal muscle during exercise, recovery from exercise, and acute respiratory acidosis.

We used 31P magnetic resonance spectroscopy to compare the response of rat skeletal muscle to three kinds of proton load. During exercise (tetanic sciatic nerve stimulation), protons from lactic acid were buffered passively and consumed by net hydrolysis of phosphocreatine (PCr). During recovery from exercise, the pH-dependent efflux of protons produced by PCr resynthesis could be partially inhibited by amiloride or 4,4'-diisothiocyanostilbene-2,2'-disulphonate (DIDS), implicating both sodium/proton and bicarbonate/chloride exchange, but was not inhibited by simultaneous respiratory acidosis. In early recovery, up to 30% of proton efflux was mediated by lactate/proton cotransport. During acute respiratory acidosis at rest, the eventual change in muscle pH was consistent with passive buffering and was unaffected by amiloride or DIDS, implying no significant contribution of proton fluxes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Comparisons of ATP turnover in human muscle during ischemic and aerobic exercise using 31P magnetic resonance spectroscopy.

To investigate human muscle bioenergetics quantitatively in vivo, we used 31P magnetic resonance spectroscopy to study the flexor digitorum superficialis of four adult males during dynamic ischemic and aerobic exercise at 0.50-1.00 W and during recovery from aerobic exercise. During exercise, changes in pH and [PCr] were larger at higher power, but in aerobic exercise neither end-exercise [ADP] nor the initial postexercise PCr resynthesis rate altered with power. In ischemic exercise we estimated total ATP synthesis from the rates of PCr depletion and glycogenolysis (inferred using an analysis of proton buffering); this was linear with power output. In aerobic exercise, again we estimated ATP synthesis rates due to phosphocreatine hydrolysis and glycogenolysis (incorporating a correction for proton efflux) and also estimated oxidative ATP synthesis by difference, using the total ATP turnover rate established during ischemic exercise. We conclude that in early exercise oxidative ATP synthesis was small, increasing by the end of exercise to a value close (as predicted) to the initial postexercise rate of PCr resynthesis. Furthermore, a plausible estimate of proton efflux during aerobic exercise can be inferred from the pH-dependence of proton efflux in recovery.

Adenosine Triphosphate↗
PubMed1994

Transsarcolemmal movement of inorganic phosphate in glucose-perfused rat heart: a 31P nuclear magnetic resonance spectroscopic study.

Fluxes of orthophosphate (Pi) across the sarcolemma may be important in myocardial metabolism, yet little is known of these in the intact heart. We used 31P NMR spectroscopy to measure net Pi fluxes from changes in the concentrations of Pi, phosphocreatine (PCr), ATP and "total phosphate" ([TP] = [PCr] + 3[ATP] + [Pi]) in the isolated perfused rat heart in response to a change in extracellular [Pi] from 2 mM to 0 mM. [Pi] decreased to 62% of control with a half-time of 6 min, while [TP] decreased with initial rate 20 mM/h, a measure of net Pi efflux. As [PCr] decreased to 83% of control, phosphorylation potential remained constant. Contractile function was unaffected. Reperfusion with 2 mM Pi reversed all changes, causing net Pi influx at 26 mM/h. Analysed according to a model of net Pi flux, these imply a sarcolemmal permeability rate constant of 13 per h. Insulin in the 2 mM Pi perfusion buffer caused a transient decrease in intracellular [Pi] to 59% of control, while [TP] increased, giving a net Pi influx of 12 mM/h and a permeability constant of 12 per h. [PCr] increased by 28% over 34 min. Thus, insulin caused Pi influx by stimulating Pi incorporation into organic phosphates, transiently decreasing intracellular [Pi] and increasing the outside-to-inside [Pi] gradient. The response to 0 mM and 2 mM Pi perfusion was unaffected by insulin. We conclude that Pi fluxes across the sarcolemma are substantial and may have implications for Pi-free tissue perfusion and clinical hypophosphataemia.

Adenosine Triphosphate↗
PubMed1994

A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson's disease.

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.

Adolescent↗
PubMed1994

Metabolic abnormalities in skeletal muscle after myocardial infarction in the rat.

1. The effect of experimental myocardial infarction on exercise and recovery of rat skeletal muscle was studied using 31P n.m.r. 4 weeks post-operatively. 2. Myocardial infarction (12 +/- 3% of left ventricular volume), insufficient to produce haemodynamic manifestations of heart failure, was without significant effect on exercise bioenergetics of skeletal muscle. 3. Citrate synthase activity was reduced by 17% in the infarcted animals and there was a marked slowing of the rate of phosphocreatine recovery after infarction (half-time 0.7 +/- 0.1 min to 1.6 +/- 0.2 min) in the absence of evidence of left ventricular failure or hypertrophy. 4. The study of recovery bioenergetics could provide a more sensitive measure of mitochondrial function than exercise, where no bioenergetic abnormality was detected. 5. Myocardial infarction can produce evidence of mitochondrial abnormality in skeletal muscle in the absence of haemodynamic compromise.

Adenosine Diphosphate↗