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Biomedical subjects

K Sahlin

Publications and source records attributed to K Sahlin.

At least 55 records · Page 3Linked to original sources
PubMed1991

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.

Aconitate Hydratase↗
PubMed1990

Adenine nucleotide depletion in human muscle during exercise: causality and significance of AMP deamination.

The predominant route for adenine nucleotide catabolism in skeletal muscle is deamination of AMP to inosine monophosphate (IMP) and ammonia (NH3). Deamination of AMP is enhanced during exercise when the capacity to rephosphorylate ADP is impaired. Thus, in human muscle the formation of IMP (NH3) during exercise is augmented under the following conditions (1) at high intensities, (2) during beta-adrenoceptor blockade, (3) during hypoxia, (4) after detraining, and (5) at low glycogen levels. The formation of IMP is related to the metabolic stress (as indicated by the degree of phosphocreatine breakdown and lactate accumulation), the rate of ATP turnover, and the fiber type composition. During maximal exercise at 100% of VO2max or sustained isometric contractions to fatigue, about 15% of the adenine nucleotide (AN) pool is degraded through deamination of AMP to IMP. It is suggested that the stimulus for increased AMP deamination is increased transient levels of ADP and AMP in the contracting muscle fiber. Deamination of AMP to IMP and NH3 provides a sink for ADP, whereby the ATP/ADP ratio and the phosphorylation potential are kept high, which may be essential for the continuation of the contraction process. This implies that the relative levels of the adenine nucleotides are more important for maintenance of adequate cellular function than the absolute concentration of ATP.

AMP Deaminase↗
PubMed1990

Muscle carnitine metabolism during incremental dynamic exercise in humans.

The changes in muscle content of carnitine and acetylcarnitine have been studied during incremental dynamic exercise. Six subjects exercised for 10 min on an ergometer at 40 and 75% of their maximal oxygen uptake (VO2 max) and to fatigue at 100% of VO2 max (about 4 min). Muscle samples were taken from the quadriceps femoris muscle at rest and after exercise. Muscle content of free carnitine was (means +/- SE) 15.9 +/- 1.7 mmol kg-1 d.wt (dry weight) at rest and remained unchanged after exercise at low intensity but decreased to 5.9 +/- 0.6 and 4.6 +/- 0.5 mmol kg-1 d.wt after exercise at 75 and 100% of VO2 max respectively. Acetylcarnine content at rest was 6.9 +/- 1.9 mmol kg-1 d.wt and increased during exercise in correspondence with the decrease in free carnitine. Muscle content of pyruvate and lactate was unchanged after exercise at 40% of VO2 max but increased at the higher intensities. The parallel increases in acetylcarnitine, pyruvate and lactate indicate that formation of acetylcarnitine is augmented when the availability of glycolytic three-carbon metabolites is high and is consistent with the idea that acetylcarnitine provides a sink for pyruvate and acetyl CoA. This could be of importance for the maintenance of an adequate level of CoA and thus function of the tricarboxylic acid cycle.

Acetyl Coenzyme A↗
PubMed1990

Influence of reduced glycogen level on glycogenolysis during short-term stimulation in man.

The relationship between muscle glycogen concentration and the rate of glycogen breakdown during short, intense contraction has been investigated in man. Prior to the experiment, muscle glycogen content was manipulated by a combination of exercise and diet, and varied from 155 +/- 19 to 350 +/- 25 mmol kg-1 dry muscle (36-81 mmol kg-1 wet wt). The quadriceps femoris muscle was stimulated electrically at a frequency of 20 Hz for 1 min. The blood flow to the leg was occluded during the experiment and muscle biopsies were taken before and after 10, 30 and 60 s stimulation. Force development and glycogenolytic rate were maintained constant during electrical stimulation and similar in all conditions, irrespective of the initial glycogen concentration. The phosphorylase a fraction was increased after 10 s stimulation, but returned to the initial values at the end of the stimulation. Muscle ATP was unaltered during the first 30 s stimulation, but decreased thereafter. The decrease in ATP was accompanied by a stoichiometric increase in inosine monophosphate. Phosphocreatine decreased during stimulation and was almost depleted at the end of stimulation. Muscle lactate and glucose 6-phosphate (Glu 6-P) increased during stimulation. None of these changes was significantly affected by the reduced glycogen contents. It is concluded that the rate of muscle glycogen breakdown is not affected by the initial glycogen level in the range of 155 +/- 19 to 350 +/- 25 mmol kg-1 dry muscle.

Adenosine Triphosphate↗
PubMed1990

Failure of glutamate dehydrogenase system to predict oxygenation state of human skeletal muscle.

In a recent study, the total tissue contents of glutamate (Glu), ammonium (NH+4), and 2-oxoglutarate (2-OG) were used to estimate changes in the mitochondrial redox state ([NAD+]/[NADH]) of contracting skeletal muscle with intact circulation [Am. J. Physiol. 253 (Cell Physiol. 22): C263-C268, 1987]. These metabolites participate in the glutamate dehydrogenase (GDH) reaction, which, based on a number of assumptions, theoretically enables calculation of the mitochondrial redox state as follows (brackets indicate concentrations): [NAD+]/[NADH] = ([NH+4] [2-OG])/[( Glu]Kapp), where Kapp is the apparent equilibrium constant for GDH. The purpose of this study was to determine whether changes in the total tissue contents of Glu, NH+4, and 2-OG could be used to predict a reduction of the mitochondrial redox state in anoxic skeletal muscle. Anoxia was induced in the quadriceps femoris muscle by 10 min of circulatory occlusion (low metabolic rate) and isometric contraction to fatigue (high metabolic rate). The mean (+/- SE) value for the metabolite ratio ([NH+4][2-OG]/[Glu]) at rest was 6 +/- 3 mmol/kg dry wt (x 10(-4]. No significant change occurred after circulatory occlusion (4 +/- 2 x 10(-4); P greater than 0.05), whereas an almost 60-fold increase was observed after isometric contraction (P less than 0.05). Because the muscle was anoxic under both conditions, a significant decrease in the metabolite ratio should have occurred. These data demonstrate that changes in total tissue contents of Glu, NH+4, and 2-OG cannot be used to estimate changes in the redox and oxygenation state of mitochondria in intact human skeletal muscle.

Adenosine Triphosphate↗
PubMed1990

Influence of ATP turnover and metabolite changes on IMP formation and glycolysis in rat skeletal muscle.

Deamination of AMP to inosine monophosphate (IMP) and NH3 is thought to be regulated by the observed increases in ADP, AMP, and H+. We have examined this hypothesis by comparing the rate of IMP accumulation in contracting and noncontracting rat skeletal muscle. The rate of IMP formation was high during ischemic contraction, and consistent with previous studies, formation of IMP was associated with high levels of muscle lactate, depletion of phosphocreatine (PCr), and increased levels of ADP and AMP. When the contraction period was followed by 5-min anoxic recovery, the metabolic changes were maintained, but no further IMP or lactate was formed. During long-term (2-4 h) anoxia, the rate of IMP formation was less than 4% of that during contraction, despite similar changes in PCr, lactate, ADP, and AMP. It is concluded that the observed changes in the intracellular chemical environment are not sufficient to explain the high rate of IMP formation during contraction but that a combination of metabolic stress and a high ATP turnover rate is required. It is suggested that a high ATP turnover rate during conditions of metabolic stress results in transient increases in ADP and AMP at the site of ATP hydrolysis and that these activate AMP deaminase and glycolysis. An alternative hypothesis is that these processes are regulated by the increase in cytosolic Ca2+ in a contracting muscle.

Adenosine Diphosphate↗
PubMed1990

Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise.

Seven subjects cycled to fatigue [75 +/- 5 (SE) min] at a work load corresponding to approximately 75% of their maximal oxygen uptake. Biopsies were taken from the quadriceps femoris muscle at rest and during exercise. Muscle glycogen decreased from a preexercise level of 445 +/- 33 mmol glucosyl units/kg dry wt to 50 +/- 14 at fatigue. The sum of the measured tricarboxylic acid cycle intermediates (TCAI = malate + citrate + fumarate + oxaloacetate) was 0.49 +/- 0.05 mmol/kg dry wt at rest, increased to 4.41 +/- 0.23 after 5 min of exercise, and then decreased continuously to 3.33 +/- 0.29 and to 2.83 +/- 0.27 mmol/kg dry wt after 40 min of exercise and at fatigue (P less than 0.05 vs. 5 min), respectively. The point of fatigue was characterized by an enhanced deamination of AMP (judged by increase in IMP) and reduced contents (vs. 5 min of exercise) of lactate, pyruvate, and alanine. In contrast, acetylcarnitine (reflects the availability of acetylunits) increased threefold at the onset of exercise and was maintained approximately at this level until fatigue. It is concluded that prolonged exercise to fatigue at moderate work loads results in glycogen depletion, energy deficiency (increased AMP deamination), reduced levels of three-carbon compounds and TCAI (compared with the initial phase of exercise) but in maintained levels of acetylunits. The present data indicate that carbohydrate depletion may impair aerobic energy production by reducing the level of TCAI.

Adenine Nucleotides↗
PubMed1990

Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease.

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.

Acetylcarnitine↗
PubMed1990

Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients.

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.

Adult↗
PubMed1990

Muscle glucose metabolism during exercise.

Substrate utilization during exercise is determined by the intensity and duration of exercise as well as by training status and the availability of substrate. The major energy source at rest and during low intensity exercise is fat oxidation while oxidation of carbohydrates and anaerobic energy utilization predominates at higher intensities. Hypoxia will induce a similar change in substrate utilization as an increase of the exercise intensity and it is suggested that O2 availability is an important determinant of muscle metabolism during exercise. Muscle glucose uptake increases during exercise and can reach values that are 30-50 times higher than at rest. The increase in muscle glucose uptake is related to the work load and the duration of the exercise, and corresponds to the output of glucose from the liver. Animal experiments have shown that muscle contraction can induce an increase in glucose uptake in the absence of insulin. Studies in man have shown that insulin and exercise at low intensity have a synergistic effect on glucose uptake, possibly due to an increased insulin inflow to the muscle. Intracellular glucose concentration is low at rest but can under certain conditions such as intensive exercise and hypoxia increase to maximum values of 3-4 mmol/l of intracellular water which demonstrates that glucose uptake under certain conditions can be in excess of the utilization of glucose.

Adenosine Triphosphate↗
PubMed1989

Glucose formation in human skeletal muscle. Influence of glycogen content.

Eight men exercised at 66% of their maximal isometric force to fatigue after prior decrease in the glycogen store in one leg (low-glycogen, LG). The exercise was repeated with the contralateral leg (control) at the same relative intensity and for the same duration. Muscle (quadriceps femoris) glycogen content decreased in the LG leg from 199 +/- 17 (mean +/- S.E.M.) to 163 +/- 16 mmol of glucosyl units/kg dry wt. (P less than 0.05), and in the control leg from 311 +/- 23 to 270 +/- 18 mmol/kg (P less than 0.05). The decrease in glycogen corresponded to a similar accumulation of glycolytic intermediates. Muscle glucose increased in the LG leg during the contraction, from 1.8 +/- 0.1 to 4.3 +/- 0.6 mmol/kg dry wt. (P less than 0.01), whereas no significant increase occurred in the control leg (P greater than 0.05). It is concluded that during exercise glucose is formed from glycogen through the debranching enzyme when muscle glycogen is decreased to values below about 200 mmol/kg dry wt.

Adult↗
PubMed1989

Oxygen deficit is not affected by the rate of transition from rest to submaximal exercise.

Five subjects cycled on an ergometer at power outputs corresponding to 20, 40, 60 and 80% of their maximal oxygen uptake (VO2 max). On one occasion the transition from rest to work was direct (D), while on the other occasion the power output was increased slowly (S) in a stepwise manner for 6-15 min prior to exercise at the predetermined intensity. Oxygen uptake (VO2) was measured, and O2 deficit and O2 debt were calculated. Oxygen deficit increased with the exercise intensities, the peak values being 2.1 +/- 0.2 and 1.9 +/- 0.1 litres (mean +/- SEM) at 80% of VO2 max after D and S respectively. No significant difference was observed in O2 deficit or O2 debt between D and S at any exercise intensity (P less than 0.05). The O2 debt was similar to the O2 deficit at 20, 40 and 60% of VO2 max but lower than the O2 deficit (P less than 0.05) at 80% of VO2 max. Femoral venous blood lactate remained unchanged at 20% of VO2 max but increased at the higher exercise intensities, reaching peak values of 7.6 +/- 0.6 and 7.4 +/- 1.1 mmol l-1 at 80% of VO2 max after D and S respectively. Blood lactate was not significantly different between D and S at any exercise intensity (P greater than 0.05). It is concluded that O2 deficit, O2 debt and blood lactate are not affected by the rate of transition from rest to submaximal exercise. The data contradict the hypothesis that O2 deficit is caused by an inadequate O2 transport at the onset of exercise.

Adult↗
PubMed1989

Formation of inosine monophosphate (IMP) in human skeletal muscle during incremental dynamic exercise.

The influence of exercise intensity on the accumulation of inosine monophosphate (IMP) in human skeletal muscle has been investigated. Ten men cycled at workloads corresponding to 40%, 75% and 100% of their maximal oxygen uptake (VO2 max). Muscle IMP was below the detection limit (less than 0.01 mmol kg-1 dry wt) at rest and after exercise at 40% of VO2 max, but increased to 0.26 +/- 0.06 (mean +/- SEM) and 3.50 +/- 0.51 mmol kg-1 dry wt after exercise at 75% and 100% of VO2 max respectively. Accumulation of IMP corresponded to a similar decrease in the total adenine nucleotide content. The muscle content of IMP was positively related to lactate and negatively related to phosphocreatine (PCr). IMP was formed in both fibre types, but the IMP content at fatigue was about twice as high in type II fibres as in type I fibres. It was concluded that the IMP content of human skeletal muscle is very low at rest and after low-intensity exercise, but increases after moderate and high-intensity exercise. In contrast to rat muscle, where deamination of AMP predominantly occurs in the fast-twitch muscle fibres, IMP is formed during exercise in both fibre types in human muscle. Accumulation of IMP appears to reflect an imbalance between the rate of utilization and the rate of regeneration of ATP.

Adenosine Monophosphate↗
PubMed1989

Hypoxaemia increases the accumulation of inosine monophosphate (IMP) in human skeletal muscle during submaximal exercise.

The effect of hypoxaemia on the muscle content of inosine monophosphate (IMP) during short-term, low-intensity exercise has been investigated. Six men cycled twice for 5 min at 120 +/- 6 W (mean +/- SE), which corresponded to approximately 50% of their maximal normoxic O2 uptake, breathing air (N) on one occasion and 11% O2 in N2 (H) on the other. Oxygen uptake at the end of the exercise period was similar between treatments. No significant difference was observed between H and N in the muscle metabolite contents at rest. Muscle content of phosphocreatine (PCr) decreased and lactate increased during exercise. Post-exercise PCr during H was 80% of the value during N (P greater than 0.05) and post-exercise muscle lactate was fourfold higher during H than during N (P less than 0.001). Post-exercise muscle content of ADP was significantly higher during H than during N (P less than 0.01), while ATP and AMP remained constant under both H and N exercise (P greater than 0.05 H vs N). IMP was not detectable in pre-exercise muscle samples (less than 0.01 mmol kg-1 dry wt) but increased during N exercise (0.03 +/- 0.01 mmol kg-1 dry wt, wt, P less than 0.05) and even more during H exercise (0.16 +/- 0.05 mmol kg-1 dry wt, P less than 0.05, H vs N). Post-exercise IMP was negatively related to PCr (r = -0.90) and positively related to lactate (r = 0.88). It is concluded that hypoxaemia results in an enhanced accumulation of IMP during submaximal exercise and that the IMP level is related to the degree of anaerobic energy utilization.

Adult↗
PubMed1989

Effect of hypoxia on glucose metabolism in human skeletal muscle during exercise.

The effect of respiratory hypoxia on muscle glucose metabolism during short-term dynamic exercise has been investigated. Eight men cycled for 5 min at 120 +/- 6 W (mean +/- SE), which corresponded to 50% of maximal O2 uptake during normoxia (N), breathing air (N) on one occasion and 11% O2 (hypoxia-H) on the other. Biopsies were taken from the quadriceps femoris muscle before and after exercise. Oxygen uptake during exercise was not affected by H. The arterial blood glucose concentration during N exercise remained constant, but increased from 4.62 +/- 0.11 mmol l(-1) at rest to 5.22 +/- 0.19 mmol l-1 at the end of H exercise (P less than 0.05 vs N exercise). The intracellular glucose content at rest was low and did not change during N exercise, but was four times higher after exercise during H vs N (P less than 0.01). Glucose 6-P increased under both conditions but significantly more during H (P less than 0.01), while glucose 1,6-P2 was not significantly different between treatments either at rest or after exercise. It is concluded that: (1) glucose uptake by skeletal muscle during short-term exercise. It is concluded that: (1) glucose uptake by skeletal muscle during short-term exercise during H is not associated with a stoichiometric glucose utilization; (2) the inhibition of hexokinase during H (evidenced by increase in muscle glucose) is due primarily to the increase in glucose 6-P; and (3) glucose 1,6-P2 is of minor importance for the regulation of contraction-mediated flux through hexokinase in human skeletal muscle.

Adult↗
PubMed1989

Effect of freeze-drying on measurements of pH in biopsy samples of the middle gluteal muscle of the horse: comparison of muscle pH to the pyruvate and lactate content.

Muscle biopsies taken after exercise, in comparison to those at rest, contain increased amounts of blood and this is a particular problem in studies of the horse. The inclusion of blood in muscle will introduce an upward bias in values of pH measured in muscle homogenates. In an attempt to control this, muscle biopsy samples of the middle gluteal from Thoroughbred horses were freeze-dried and dissected free of blood before determination of pH. Following exercise, muscle pH measured after freeze-drying was similar to that measured in homogenates prepared from frozen samples. In contrast, freeze-drying appeared to increase muscle pH in samples taken at rest. This was probably the result of loss of CO2 during freeze-drying. Muscle pH determined in freeze-dried samples taken at rest and after exercise was linearly related to pyruvate and lactate content (P less than 0.001). It is concluded that muscle samples taken after exercise can be freeze-dried and dissected free from blood before determination of pH, whereas this procedure will cause an alkaline shift in samples taken at rest.

Animals↗