Search PubMed⌕ Search

Biomedical subjects

R A Challiss

Publications and source records attributed to R A Challiss.

At least 127 records · Page 7Linked to original sources
PubMed1989

Acute and chronic effects of strenuous exercise on glucose metabolism in isolated, incubated soleus muscle of exercise-trained rats.

Male and female Wistar rats were exercise-trained for 6 or 11 weeks respectively, to examine the effects of acute exercise or exercise training per se on insulin-stimulated glucose utilization in soleus muscles isolated and incubated in vitro. The maximal activities of hexokinase and 2-oxoglutarate dehydrogenase were significantly elevated (by greater than 50%) in gastrocnemius muscle of exercise-trained male and female rats, indicating an adaptation to the training regime. No significant differences in any of the variables studied were observed between appropriately matched male and female rats. There were no significant differences in the sensitivity or responsiveness of the rates of lactate formation or glycogen synthesis in soleus muscles isolated from exercise-trained and sedentary animals at rest (exercise-trained animals were studied 40 h after the last exercise bout). On the other hand, acute exercise caused significant changes in soleus muscle glucose metabolism. Basal and insulin-stimulated rates of glycogen synthesis were significantly elevated in soleus muscles incubated from both sedentary and exercise-trained rats immediately after an exercise bout. In addition, the responsiveness of glucose utilization to insulin in soleus muscles from exercise-trained rats was significantly increased after acute exercise. The results indicate that significant changes in the control of glucose metabolism by insulin in soleus muscle occur as a result of an acute exercise bout, while no adaptive changes in insulin sensitivity occur in soleus muscle after exercise training.

Animals↗
PubMed1989

Bioenergetic changes during contraction and recovery in diabetic rat skeletal muscle.

Phosphorus nuclear magnetic resonance (31P-NMR) spectroscopy was used to assess the effects of hypoinsulinemia on skeletal muscle during contraction in vivo. Five groups of rats were studied: age-matched (CONA) and weight-matched (CONW) nondiabetic controls; rats given streptozotocin 21 days before study (UD); diabetic rats treated with insulin for 21 days (ITD); and insulin-treated diabetic rats with insulin treatment withheld for 72 h before study (IWD). Both UD and IWD had similar alterations in plasma substrate concentrations and an impairment in the rate of glycogen resynthesis after the stimulation protocol compared with ITD, CONA, and CONW. Pyruvate oxidation was decreased by 30-40% in mitochondria isolated from gastrocnemius of the UD group, whereas no significant decrease was observed for mitochondria from the IWD (or ITD) group(s). In UD, maintenance of gastrocnemius muscle isometric twitch tension at 1 Hz required exaggerated decreases in phosphocreatine (PCr) concentration and pH; at 5 Hz, muscle performance declined significantly, and intracellular pH decreased to lower values than observed for the control groups; during recovery, no impairment of PCr resynthesis was observed. We conclude that in skeletal muscle of UD 1) at 1 Hz there is an increased reliance on glycolytic mechanisms of ATP resynthesis and 2) at 5 Hz force failure may occur because of the decreased rate of pyruvate utilization.

Animals↗
PubMed1988

A 31P-NMR study of the acute effects of altered beta-adrenoceptor stimulation on the bioenergetics of skeletal muscle during contraction.

The effects of acute administration of a beta-adrenoceptor agonist (isoprenaline) or antagonist (propranolol) on skeletal muscle contraction and metabolism in the rat have been studied in vivo using 31P-nuclear magnetic resonance spectroscopy and conventional metabolite analysis. In resting muscle, isoprenaline caused a three-fold increase in cyclic AMP concentration, whereas propranolol decreased cyclic AMP concentration by 40%. Isometric contraction of gastrocnemius muscle at a frequency of 4 Hz was caused by supramaximal sciatic nerve stimulation. Altered beta-adrenoceptor stimulation had no effect on contractile performance at any time during the 30 min stimulation period. During the initial stimulation period (0-4 min) intracellular pH decreased to significantly lower values in the isoprenaline-treated animals (6.24 +/- 0.03) compared to either the control (6.44 +/- 0.08) or propranolol-treated (6.42 +/- 0.08) groups. During the subsequent stimulation period (after 15-30 min stimulation at 4 Hz), pH recovered in all experimental groups to values greater than 6.90 and phosphocreatine concentration achieved a constant level at 35-40% of resting values. Calculation of free ADP concentrations using 31P-NMR determined metabolite concentrations and the creatine phosphokinase equilibrium showed that at similar tension development, [ADP]free varied between the three experimental groups; with the lowest (47 +/- 4 microM) and highest (73 +/- 4 microM) values being calculated for the beta-adrenoceptor agonist- and antagonist-treated groups respectively. Upon termination of stimulation, recovery of phosphocreatine concentration to pre-stimulation values was rapid and similar in all experimental groups. However, gastrocnemius muscle ATP concentration, determined by 31P-NMR and analysis of freeze-clamped muscle, was lower in the isoprenaline-treated group. This study has shown that although altered beta-adrenoceptor stimulation had no effect on contractile performance, significant changes in muscle metabolism were observed in vivo; these effects are discussed with respect to the role of beta-adrenoceptors in skeletal muscle.

Adenine Nucleotides↗
PubMed1988

Mass measurements of inositol(1,4,5)trisphosphate in rat cerebral cortex slices using a radioreceptor assay: effects of neurotransmitters and depolarization.

The specific binding of [3H] and [32P]Ins(1,4,5)P3 to a particulate preparation of bovine adrenal cortex has been used as a radioreceptor assay to determine the concentration of Ins(1,4,5)P3 in agonist- and depolarization-stimulated rat cerebral cortex slices. The resting concentration of Ins(1,4,5)P3 in slices that had been preincubated in a physiological medium was 18.8 +/- 2.6 pmol/mg prot. Carbachol evoked a rapid and dose-related increase in the concentration of Ins(1,4,5)P3. Maximal stimulation (80%) was already seen at the earliest point (10 sec) examined and was maintained for at least 5 min. The EC50 for carbachol was 75 +/- 17 microM and the response was totally suppressed by the muscarinic antagonist atropine. A direct comparison in the same slices was made between mass determinations and [3H]Ins(1,4,5)P3 and [3H]Ins(1,3,4)P3 accumulation determined by h.p.l.c. Although an identical time course was observed for cold and radiolabelled Ins(1,4,5)P3, the greater stimulation of [3H]Ins(1,4,5)P3 may indicate changes in specific radioactivity. Of a variety of other receptor agonists studied, only the glutamate receptor agonist quisqualate, and noradrenaline significantly increased the mass of Ins(1,4,5)P3 in cerebral cortical slices. However, depolarizing concentrations of K+ were as effective as carbachol at elevating this second messenger.

Adrenal Cortex↗
PubMed1988

Effects of hyperthyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.

1. The effects of hyperthyroidism on the sensitivity and responsiveness of glycolysis and glycogen synthesis to insulin were investigated in the isolated incubated soleus muscle of the rat. 2. Hyperthyroidism, which was induced by administration of tri-iodothyronine (T3) to rats for 2, 5 or 10 days, increased fasting plasma concentrations of glucose, insulin and free fatty acids. 3. Administration of T3 for 2 or 5 days increased the rates of glycolysis at all insulin concentrations studied: this was due to increased rates of both glucose phosphorylation and glycogen breakdown, but there was no effect of T3 on the sensitivity of glycolysis to insulin. However, administration of T3 for 10 days increased the sensitivity of the rate of glycolysis to insulin. 4. The concentration of adenosine in the gastrocnemius muscles of the rats was not different from controls after 5 days, but it was markedly decreased after 10 days of T3 administration. If these changes are indicative of changes in the soleus muscle, the increased sensitivity of glycolysis to insulin found after 10 days' T3 administration could be due to the decrease in the concentration of adenosine. 5. Administration of T3 decreased the sensitivity of glycogen synthesis to insulin and the glycogen content of the soleus muscles. This may explain the decreased rates of non-oxidative glucose disposal found in spontaneous and experimental hyperthyroidism in man. 6. The rates of glucose oxidation did not change after 2 days, but they were increased after 5 and 10 days of T3 administration.

Adenosine↗
PubMed1988

An investigation of the beta-adrenoceptor that mediates metabolic responses to the novel agonist BRL28410 in rat soleus muscle.

The beta-adrenoceptor agonist BRL26830A selectively stimulates metabolic rate in the rat and this thermic effect is resistant to blockade by propranolol. These effects of BRL26830A are partly due to selective stimulation by its metabolite BRL28410, of brown adipocyte beta-adrenoceptors, these receptors being resistant to propranolol. To investigate whether the metabolic effects of BRL28410 in skeletal muscle are also mediated by atypical beta-adrenoceptors, the potencies of BRL28410 and isoprenaline were compared for beta-adrenoceptor mediated responses in rat stripped soleus muscle. In addition, pA2 values for antagonism by propranolol of these responses were determined. Isoprenaline had similar EC50 values for stimulation of lactate formation (4.3 X 10(-9) M) and inhibition of glycogen synthesis (3.4 X 10(-9) M) and these values are similar to its reported EC50 values for stimulation of atrial rate (beta 1-adrenoceptor-mediated) and relaxation of the uterus (beta 2-adrenoceptor-mediated). BRL28410 had similar EC50 values for stimulation of lactate formation (3.7 X 10(-6) M) and inhibition of glycogen synthesis (3.8 X 10(-6) M). These values are only about two-fold less than reported values for relaxation of the uterus, but ten-fold less than reported values for stimulation of atrial rate. The pA2 value of dl-propranolol for antagonism of the effect of isoprenaline on glycogen synthesis (8.38 +/- 0.13) was in the range expected for beta 1- or beta 2-adrenoceptors, but with BRL28410 as agonist the pA2 value was about one unit lower (7.39 +/- 0.11). The beta-adrenoceptors that mediate the metabolic effects of BRL28410 in soleus muscle therefore differ from those that mediate atrial rat, uterine relaxation and adipocyte lipolysis. In addition, the low pA2 value of dl-propranolol versus BRL28410 in rat soleus muscle, which contrasts with the normal pA2 value previously reported for guinea-pig trachea, suggests that beta 2-adrenoceptors in these two tissues can be differentiated with suitable pharmacological agents.

Animals↗
PubMed1988

Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat.

1. Soleus, extensor digitorum longus (EDL) or hemi-diaphragm muscles of the rat were incubated in the presence of insulin and rates of the processes of glycolysis and glycogen synthesis were measured. 2. The concentrations of insulin required to cause half-maximal stimulation of glycolysis in both soleus and EDL preparations were significantly decreased by the presence of adenosine deaminase in the medium. 3. Adenosine deaminase increased the sensitivity of the process of hexose transport to insulin (in an identical manner to the change in sensitivity of glycolysis) in the EDL preparation. 4. None of the adenosine mediated effects on insulin-stimulated rates of glycolysis were observed in the hemi-diaphragm preparation or on the rates of glycogen synthesis in any of the three muscle preparations. 5. Therefore, changes in the adenosine system in skeletal muscle influence insulin sensitivity regardless of fibre type composition of the muscle.

3-O-Methylglucose↗
PubMed1988

An animal model of mitochondrial myopathy: a biochemical and physiological investigation of rats treated in vivo with the NADH-CoQ reductase inhibitor, diphenyleneiodonium.

Chronic administration of the NADH-CoQ reductase inhibitor, diphenyleneiodonium to rats at two dose levels, 1.0 and 1.5 mg/kg per day, caused a 40% and 60% reduction, respectively, in the in vitro rate of NAD-linked respiration by skeletal muscle mitochondria. At the highest dose, muscle fatigue, lactic acidosis and an over-utilization of phosphocreatine was observed in the gastrocnemius muscle during mild stimulation of 1 Hz frequency. The resynthesis of phosphocreatine following muscle stimulation was about 2 fold slower in the treated animal group. At the low dose, no significant biochemical changes were observed during muscle stimulation at 4 Hz. The results are discussed in terms of skeletal muscle "oxidative reserve", twitch tension maintenance and the relevance to the human diseased state of mitochondrial myopathy.

Acidosis↗
PubMed1988

Integration of carbohydrate and lipid metabolism in skeletal muscle during postnatal development.

In the adult, muscle metabolism represents a large drain of energetic substrates. The newborn has to provide additional energy to its muscles in order to ensure a rapid growth. However, since during the neonatal period the newborn is fed with a high-fat low-carbohydrate diet, i.e., milk, the newborn must also spare glucose for organs which are obligatory glucose consumers such as the brain. Thus, regulation of energetic substrate utilisation by muscle is of upmost importance for postnatal metabolic homeotasis. In the human, fibre types at birth can already be histochemically classified as adult types and the proportional distributions of each fibre-type approximate those seen in the adult. On the other hand, glycolytic and oxidative maximal enzyme activities are lower than adult levels. In the rat, the capacity for glucose utilisation in muscles is low at birth, reaches a peak at weaning and subsequently decreases. During the suckling period, the concentration of lipid-derived substrates is high as well as the muscle capacity for their oxidation; moreover, insulin concentration is low and insulin sensitivity of muscle glucose utilization is also reduced. Thus, during the suckling period, fuel availability and insulin concentrations, as well as tissue sensitivity towards the hormone, favour the limitation of glucose utilisation by skeletal muscles.

Animals↗
PubMed1988

Spatial heterogeneity of metabolism in skeletal muscle in vivo studied by 31P-NMR spectroscopy.

Phase-modulated rotating-frame imaging, a localization technique for phosphorus nuclear magnetic resonance spectroscopy, has been applied to obtain information on heterogeneity of phosphorus-containing metabolites in skeletal muscle of the rat in vivo. The distal muscles of the rat hindlimb have been studied at rest and during steady-state isometric twitch contraction; the use of a transmitter surface coil and an electrically isolated, orthogonal receiver Helmholtz coil ensure accurate spatial assignment (1 mm resolution). At rest, intracellular pH was higher and PCr/(PCr + Pi) was lower in deeper muscles compared with superficial muscle of the distal hindlimb. Upon steady-state stimulation, the relatively more alkaline pH of deep muscle was maintained, whereas greater changes in PCr/(PCr + Pi) and Pi/ATP occurred in the superficial muscle layer. This method allows rapid (75 min for each spectral image) acquisition of quantitative information on metabolic heterogeneity in vivo.

Adenosine Triphosphate↗
PubMed1988

Circadian rhythm in sensitivity of glucose metabolism to insulin in rat soleus muscle.

This study determined whether the sensitivity of glucose metabolism to insulin in skeletal muscle varies during a 24-h period. Soleus muscles were isolated from ad libitum-fed rats killed at 0900, 1600, 2100, and 0300. The animal house was illuminated between 0800 and 2000. The sensitivities of glycolysis (which is an excellent index of glucose transport) and glycogen synthesis to insulin were greatest in muscles isolated at 0900 and 2100. Marked decreases in sensitivities of both processes to insulin were observed in muscles isolated at 0300 and 1600, which are times halfway through the feeding and postabsorptive periods, respectively. Hence, this study demonstrates circadian changes in the sensitivity of glucose utilization by skeletal muscle to insulin, which may be important in control of blood glucose concentration. Glycogen levels in skeletal muscles were highest at 0300 and lowest at 2100; hepatic glycogen content reached a peak at 0900, and the lowest content was measured at 2100. The liver glycogen level was increased by only 15% midway into the feeding period (i.e., 0300). This suggests that muscle glycogen may act as a temporary store of glucose residues during the feeding period; it stores glycogen in the first half of the feeding period but during the second half some muscle glycogen is converted to lactate, which acts as a precursor for hepatic gluconeogenesis.

Animals↗
PubMed1987

Effects of dexamethasone treatment on insulin-stimulated rates of glycolysis and glycogen synthesis in isolated incubated skeletal muscles of the rat.

1. Rats were treated with dexamethasone for 4 days before measurement of the rates of lactate formation [which is an index of hexose transport; see Challiss, Lozeman, Leighton & Newsholme (1986) Biochem. J. 233, 377-381] and glycogen synthesis in response to various concentrations of insulin in isolated incubated soleus and extensor digitorum longus muscle preparations. 2. The concentration of insulin required to stimulate these processes half-maximally in soleus and extensor digitorum longus muscles isolated from control rats was about 100 muunits/ml. 3. Dexamethasone increases the concentration of insulin required to stimulate glycolysis half-maximally in soleus and extensor digitorum longus preparations to 250 and 300 muunits/ml respectively. The respective insulin concentrations necessary to stimulate glycogen synthesis half-maximally were about 430 and 370 muunits/ml for soleus and extensor digitorum longus muscle preparations isolated from steroid-treated rats. 5. Dexamethasone treatment did not change the amount of insulin bound to soleus muscle.

Animals↗
PubMed1987

A 31P-n.m.r. study of the acute effects of beta-blockade on the bioenergetics of skeletal muscle during contraction.

1. The effects of beta-adrenoceptor antagonist administration on skeletal muscle contractile performance and bioenergetics in vivo have been investigated during unilateral sciatic nerve stimulation in the rat. 2. Two muscle stimulation protocols have been used: supramaximal stimulation at 4 Hz, or incremental supramaximal stimulation at 1, 2 and 4 Hz. Changes in high-energy phosphate concentrations were followed using 31P-n.m.r., and gastrocnemius muscle twitch characteristics were monitored continuously. 3. Under all conditions investigated, DL-propranolol administration (2.5 mg/kg body wt.) caused a significant decrease in cyclic AMP concentrations in resting and stimulated gastrocnemius muscle, prevented an increase in heart rate upon muscle stimulation, but did not affect plasma glucose, fatty acid or lactate concentrations in comparison with values obtained in control experiments. 4. Administration of DL-propranolol 5 min or 35 min before unilateral stimulation of 4 Hz had no effect on changes in muscle phosphocreatine, ATP or Pi concentrations, intracellular pH or contractile performance. 5. In contrast, animals receiving DL-propranolol 5 min before unilateral stimulation of 1, 2 and 4 Hz showed a significant deterioration in gastrocnemius muscle tension development during 2 and 4 Hz stimulation compared with control animals. Concurrent with this change in contractile performance was a higher muscle concentration of phosphocreatine, a lower concentration of Pi and no significant change in intramuscular pH compared with control experiments. 6. The changes in muscle performance and bioenergetics observed during the incremental stimulation protocol were not observed when D-propranolol was administered and could be completely circumvented by a short period of muscle stimulation of 4 Hz prior to initiation of the incremental stimulation protocol. 7. Mechanisms are discussed which may account for the failure of gastrocnemius muscle to generate the expected force during the incremental stimulation protocol in the presence of beta-blockade.

Adenine Nucleotides↗
PubMed1987

Effects of prolonged elevation of plasma adrenaline concentration in vivo on insulin-sensitivity in soleus muscle of the rat.

1. Prolonged elevation of the plasma adrenaline concentration was produced in rats by implantation of adrenaline-releasing retard-tablets. With this technique, a hyperadrenalinaemic state is maintained for at least 5 days. 2. At 6 h after implantation of the retard-tablet it was found that plasma glucose and fatty acid concentrations increased and insulin concentration decreased compared with values obtained from placebo-tablet-implanted rats. Administration of a subcutaneous glucose load demonstrated an impaired glucose tolerance in vivo, and incubation of soleus muscle strips from 6 h-hyperadrenalinaemic rats in vitro demonstrated a decreased sensitivity of the rates of glycolysis and glucose transport to insulin. 3. The sensitivities of the rates of glycolysis, glucose transport and glycogen synthesis to insulin were determined for the incubated soleus muscle preparation isolated from animals after 48 h, 72 h and 120 h duration of hyperadrenalinaemia. At 48 h after retard-tablet implantation, the sensitivity of the processes of glucose transport and glycolysis was decreased; at 72 h, the insulin-sensitivities of the rates of glycolysis and glucose transport in skeletal muscle were similar to those determined for control animals; at 120 h, however, the sensitivities of the processes of glucose transport and glycolysis were both statistically significantly increased. In contrast, no changes in the sensitivity of the process of glycogen synthesis were observed at any of the time intervals studied. 4. The possible biochemical basis for the observed changes in skeletal-muscle insulin-sensitivity with prolonged hyperadrenalinaemia is discussed.

3-O-Methylglucose↗
PubMed1987

Hormonal regulation of the rate of the glycogen/glucose-1-phosphate cycle in skeletal muscle.

A method is presented which allows simultaneous estimation of rates of glycogen synthesis and glycogenolysis in an isolated incubated skeletal muscle, thus allowing measurement of the glycogen/glucose-1-phosphate substrate cycling rate. In the absence of hormonal additions, the measured rates of glycogen synthesis and breakdown were similar [respectively, 0.54 +/- 0.12 (8) and 0.74 +/- 0.10 (8) mumol glucosyl equiv. h-1 (g tissue)-1]. Incremental addition of insulin stimulated glycogen synthesis up to threefold and reduced glycogenolysis by about sevenfold; the half-maximally effective concentration of insulin on both processes was about 100 microU/ml (0.7 nM). Incremental addition of adrenaline (in the presence of 1 mU insulin/ml) caused a dramatic increase in the glycogenolytic rate (about 15-fold), but a much less marked inhibition of glycogen synthetic rate. In addition to hormonal manipulation of the muscle preparation in vitro, the effects of cold exposure, the hyperthyroid state, a single exercise bout and exercise-training of animals in vivo on the rates of glycogen synthesis and breakdown in the isolated incubated muscle preparation have been investigated. Significant changes in measured glycogen synthesis, breakdown and glycogen/glucose-1-phosphate cycling have been observed, both under basal conditions and in response to hormonal additions in vitro. The results are discussed with respect to the possible physiological importance of this substrate cycle.

Adaptation, Physiological↗
PubMed1987

Effects of chronic administration of vanadate to the rat on the sensitivity of glycolysis and glycogen synthesis in skeletal muscle to insulin.

Male Wistar rats were given sodium orthovanadate in their drinking water for at least 14 days. This treatment increased the hypoglycaemic effect of intravenously administered insulin and increased the sensitivity of isolated soleus muscle strips to insulin with respect to both glycolytic and glycogen synthetic rates. This effect of chronic vanadate administration was shown not to be a consequence of a change in the insulin binding characteristics of soleus muscle. It is suggested that these changes may be brought about by the interaction of vanadate with insulin-mediated alterations in tyrosine kinase/phosphotyrosyl phosphatase activities.

Animals↗