glycogen and Acidosis--Lactic

This article describes the physiologic and neural mechanisms that cause neuromuscular fatigue in racquet sports: table tennis, tennis, squash, and badminton. In these intermittent and dual activities, performance may be limited as a match progresses because of a reduced central activation, linked to changes in neurotransmitter concentration or in response to afferent sensory feedback. Alternatively, modulation of spinal loop properties may occur because of changes in metabolic or mechanical properties within the muscle. Finally, increased fatigue manifested by mistimed strokes, lower speed, and altered on-court movements may be caused by ionic disturbances and impairments in excitation-contraction coupling properties. These alterations in neuromuscular function contribute to decrease in racquet sports performance observed under fatigue.

Topics: Acidosis, Lactic; Adaptation, Physiological; Energy Metabolism; Glucose; Glycogen; Humans; Muscle Contraction; Muscle Fatigue; Muscle, Skeletal; Peripheral Nerves; Racquet Sports

The crucial role of muscle glycogen as a fuel during prolonged exercise is well established, and the effects of acute changes in dietary carbohydrate intake on muscle glycogen content and on endurance capacity are equally well known. More recently, it has been recognized that diet can also affect the performance of high-intensity exercise of short (2-7 min) duration. If the muscle glycogen content is lowered by prolonged (1-1.5 h) exhausting cycle exercise, and is subsequently kept low for 3-4 days by consumption of a diet deficient in carbohydrate (< 5% of total energy intake), there is a dramatic (approximately 10-30%) reduction in exercise capacity during cycling sustainable for about 5 min. The same effect is observed if exercise is preceded by 3-4 days on a carbohydrate-restricted diet or by a 24 h total fast without prior depletion of the muscle glycogen. Consumption of a diet high in carbohydrate (70% of total energy intake from carbohydrate) for 3-4 days before exercise improves exercise capacity during high-intensity exercise, although this effect is less consistent. The blood lactate concentration is always lower at the point of fatigue after a diet low in carbohydrate and higher after a diet high in carbohydrate than after a normal diet. Even when the duration of the exercise task is kept constant, the blood lactate concentration is higher after exercise on a diet high in carbohydrate than on a diet low in carbohydrate. Consumption of a low-carbohydrate isoenergetic diet is achieved by an increased intake of protein and fat. A high-protein diet, particularly when combined with a low carbohydrate intake, results in metabolic acidosis, which ensues within 24 h and persists for at least 4 days. This appears to be the result of an increase in the circulating concentrations of strong organic acids, particularly free fatty acids and 3-hydroxybutyrate, together with an increase in the total plasma protein concentration. This acidosis, rather than any decrease in the muscle glycogen content, may be responsible for the reduced exercise capacity in high-intensity exercise; this may be due to a reduced rate of efflux of lactate and hydrogen ions from the working muscles. Alternatively, the accumulation of acetyl groups in the carbohydrate-deprived state may reduce substrate flux through the pyruvate dehydrogenase complex, thus reducing aerobic energy supply and accelerating the onset of fatigue.

Topics: Acidosis, Lactic; Ammonia; Dietary Carbohydrates; Dietary Proteins; Energy Intake; Exercise; Fatigue; Glycogen; Glycolysis; Humans; Muscle, Skeletal; Physical Endurance

Topics: Acidosis, Lactic; Adult; Child; Citric Acid Cycle; Female; Gluconeogenesis; Glycogen; Humans; Infant, Newborn; Lactates; Lactic Acid; Male; Metabolism, Inborn Errors; Mitochondria; Pyruvate Carboxylase Deficiency Disease; Pyruvates

Mice homozygous for the human GRACILE syndrome mutation (Bcs1l

Topics: Acidosis, Lactic; Animals; Blood Glucose; Cholestasis; Electron Transport; Electron Transport Complex III; Fasting; Female; Fetal Growth Retardation; Gluconeogenesis; Glycogen; Hemosiderosis; Hepatocytes; Homozygote; Hypoglycemia; Lipid Mobilization; Liver; Male; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Renal Aminoacidurias; Triglycerides

Topics: Acidosis, Lactic; Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver; Liver Diseases; Liver Function Tests; Predictive Value of Tests

A defective mitochondrial respiratory chain complex (DMRC) causes various metabolic disorders in humans. However, the pathophysiology of DMRC in the liver remains unclear. To understand DMRC pathophysiology in vitro, DMRC-induced pluripotent stem cells were generated from dermal fibroblasts of a DMRC patient who had a homoplasmic mutation (m.3398T→C) in the mitochondrion-encoded NADH dehydrogenase 1 (MTND1) gene and that differentiated into hepatocytes (DMRC hepatocytes) in vitro. DMRC hepatocytes showed abnormalities in mitochondrial characteristics, the NAD(+)/NADH ratio, the glycogen storage level, the lactate turnover rate, and AMPK activity. Intriguingly, low glycogen storage and transcription of lactate turnover-related genes in DMRC hepatocytes were recovered by inhibition of AMPK activity. Thus, AMPK activation led to metabolic changes in terms of glycogen storage and lactate turnover in DMRC hepatocytes. These data demonstrate for the first time that energy depletion may lead to lactic acidosis in the DMRC patient by reduction of lactate uptake via AMPK in liver.

Topics: Acidosis, Lactic; AMP-Activated Protein Kinases; Cell Differentiation; DNA, Mitochondrial; Electron Transport; Enzyme Activation; Fibroblasts; Glycogen; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Infant; Lactic Acid; Liver; Male; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Diseases; Mutation; NADH Dehydrogenase; Point Mutation

D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2'-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASO-treated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.

Topics: Acidosis, Lactic; Animals; Antiporters; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Glucagon; Glucose-6-Phosphatase; Glycogen; Glycogen Storage Disease; Hyperlipidemias; Hyperuricemia; Hypoglycemia; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Monosaccharide Transport Proteins; Oligoribonucleotides, Antisense; RNA, Messenger

To investigate the skeletal muscle mitochondrial function in HIV-infected patients with lipodystrophy or elevated p-lactate levels.. Eight HIV patients treated with highly active antiretroviral therapy, with lipodystrophy or elevated p-lactate, and eight healthy controls were exposed to incremental exercise until exhaustion.. Blood samples and gas analysis were performed at rest, during exercise and in recovery. Oxygen consumption, workload and blood lactate were assessed. Before and immediately after exercise muscle biopsies were obtained, in which citrate synthase (CS), hydroxyacyl-coenzyme A dehydrogenase (HD), glycogen and nucleotides were measured.. Maximal workload was significantly lower in patients compared with controls [171 Watt (88-206) versus 235 Watt (118-294) P = 0.05]. A trend towards lower maximal oxygen consumption (VO(2max)) was detected in patients [2136 ml/min (1221-2598) versus 2985 ml/min (1506-3959) P = 0.11]. Patients had significantly elevated levels of blood lactate at rest [1.55 mmol/l (1-2.5) versus 0.8 mmo/l (0.37-1.1) P < 0.01), but no significant difference in maximal blood-lactate values was found. The decline in blood lactate in the recovery period was similar between groups. There was no significant difference in CS, HD, glycogen or nucleotides.. The significantly lower working capacity and the trend towards reduced VO(2max) in patients could be caused by mitochondrial dysfunction, but may also be caused by impaired physical fitness. The similar levels of nucleotides, CS, HD, and glycogen and the normal increase in blood lactate during exercise indicates a normal oxidative phosphorylation. No evidence of serious damage to skeletal muscle mitochondrial function was found.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acidosis, Lactic; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biopsy; Body Composition; Citrate (si)-Synthase; Exercise Test; Exercise Tolerance; Female; Glycogen; HIV Infections; Humans; Lactates; Lipodystrophy; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Nucleotides; Oxygen Consumption; Pyruvates; Reverse Transcriptase Inhibitors

In our previous work, we routinely observed that a combined cocaine-exercise challenge results in an abnormally rapid muscle glycogen depletion and excessive blood lactacidosis. These phenomena occur simultaneously with a rapid rise in norepinephrine and in the absence of any rise in epinephrine. We postulated that norepinephrine may cause vasoconstriction of the muscle vasculature through activation of alpha-1 receptors during cocaine-exercise, thus inducing hypoxia and a concomitant rise in glycogenolysis and lactate accumulation. To test this hypothesis, rats were pretreated with the selective alpha-1-receptor antagonist prazosin (P) (0.1 mg/kg iv) or saline (S). Ten minutes later, the animals were treated with cocaine (-C) (5 mg/kg iv) or saline (-S) and run for 4 or 15 min at 22 m/min at 10% grade. In the S-S group, glycogen content of the white vastus lateralis muscle was unaffected by exercise at both time intervals, whereas in S-C rats glycogen was reduced by 47%. This effect of cocaine-exercise challenge was not attenuated by P. Similarly, blood lactate concentration in S-C rats was threefold higher than that of S-S after exercise, a response also not altered by pretreatment with P. On the basis of these observations, we conclude that the excessive glycogenolysis and lactacidosis observed during cocaine-exercise challenge is not the result of vasoconstriction secondary to norepinephrine activation of alpha-1 receptors.

Topics: Acidosis, Lactic; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Cocaine; Glycogen; Lactic Acid; Male; Muscle, Skeletal; Physical Conditioning, Animal; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Time Factors

Cortical metabolites and regional cerebral intracellular pH (pHi) were measured in normoglycemic (NM), acute hyperglycemic (AH), and chronic hyperglycemic (CH, 2 week duration, streptozotocin-induced) Wistar rat brains during cardiac arrest and resuscitation. During total ischemia in AH and CH rats (plasma glucose approximately 30 mM), cortical ATP, PCr, glucose, and glycogen all fell significantly as expected. Lactate levels increased dramatically in association with a concomitant intracellular acidosis. Although lactate reached higher concentrations in AH and CH than NM, pHi was significantly lower only in the AH group. With 5 min of reperfusion, all groups recovered to near baseline in all variables, though lactate remained elevated. In a separate aspect of the study, animals from each experimental group were allowed to recover for 4 days following resuscitation, with outcome being gauged by mortality rate and hippocampal CA1 neuron counts. NM survival rate was significantly better than AH and CH. In particular, no CH rats survived for 4 days despite rapid initial recovery. After 4 days, the AH group had suffered significantly greater CA1 neuron loss than the NM rats. In summary, our research identified differences in intra-ischemic acid-base status in the two hyperglycemic groups, suggesting that chronic hyperglycemia may alter the brain's buffering capacity. These observations may account for differences between acutely and chronically hyperglycemic subjects regarding outcome, and they suggest that factors other than hydrogen ion production during ischemia are responsible for modulating outcome.

Topics: Acidosis, Lactic; Acute Disease; Adenosine Triphosphate; Animals; beta-Galactosidase; Blood Glucose; Cardiopulmonary Resuscitation; Cell Survival; Cerebral Cortex; Chronic Disease; Diabetes Mellitus, Experimental; Energy Metabolism; Glycogen; Heart Arrest; Hippocampus; Hydrogen-Ion Concentration; Hyperglycemia; Image Processing, Computer-Assisted; Ischemic Attack, Transient; Lactase; Male; Neurons; Rats; Rats, Wistar

Both steroids and hemorrhage may affect the hepatic energy metabolism. The effects of steroids (5 mg.kg-1 of methylpredonisolone, 50 mg.kg-1 of methylpredonisolone, 25 mg.kg-1 of hydrocortisone and 250 mg.kg-1 of hydrocortisone) on hepatic ATP level and L/P ratio were evaluated in rats under acute hemorrhage. There were no significant differences in the hepatic ATP levels and L/P ratio among 5 groups. However, the base excess in 3 steroid groups (50 mg.kg-1 of methylpredonisolone, 25 mg.kg-1 of hydrocortisone and 250 mg.kg-1 of hydrocortisone) was significantly higher than that in the control group. This result suggests that steroids may improve the metabolic acidosis during acute hemorrhage.

Topics: Acidosis, Lactic; Acute Disease; Adenosine Triphosphate; Animals; Anti-Inflammatory Agents; Glycogen; Hemorrhage; Hydrocortisone; Lactic Acid; Liver; Male; Methylprednisolone; Pyruvic Acid; Rats; Rats, Wistar

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.

Topics: Acidosis, Lactic; Animals; Body Temperature Regulation; Dichloroacetic Acid; Disease Models, Animal; Enzyme Activation; Glycogen; Lactates; Liver; Male; Muscle Fatigue; Muscle, Skeletal; Oxidation-Reduction; Physical Endurance; Physical Exertion; Pyruvate Dehydrogenase Complex; Pyruvates; Rats; Rats, Sprague-Dawley; Running; Time Factors

During an incremental exercise test after a preceding bout of maximum exercise, blood lactate initially decreases to an individual minimum and then increases again. To determine whether this minimum represents an individual equilibrium between lactate production and catabolism during constant load exercise, the following field tests were performed: in 25 runners and five basketball players (series 1) the speed corresponding to the individual lactate minimum (LM) was measured in test 1 (incremental test after exercise induced lactic acidosis). On two occasions, two constant speed runs over 8 km were performed, one using the LM speed (LMS) (test 2), and another at a running speed of 0.2 m.s-1 above the LMS (test 3). Results of runners/basketball players: blood lactate concentration ([Lac-]B) in test 2 changed from 3.6/4.9 mmol.l-1 to 4.0/4.9 mmol.l-1 during the last 4.8 km, in test 3 from 4.6/4.6 mmol.l-1 to 6.5/6.9 mmol.l-1. These results indicate: 1) the LM speed in test 1 corresponds to a maximum lactate steady state speed during constant load exercise; 2) only a slight speed increase above the LM speed results in continuous marked [Lac-]B increase and earlier exhaustion. Variation of the increment duration in 13 males (series 2) shows no change of the LMS using 800-m and 1200-m increments (4.49 and 4.44 m.s-1) but a marked shift to higher speed using 400-m increments (4.96 m.s-1). Effects of low muscle glycogen stores on the LMS were determined in 10 males (series 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis, Lactic; Adult; Anaerobic Threshold; Analysis of Variance; Basketball; Exercise; Exercise Test; Female; Glycogen; Glycolysis; Heart Rate; Humans; Lactates; Male; Muscles; Physical Endurance; Running

To differentiate the effects of high energy phosphates, pH, and [H2PO4-] on skeletal muscle fatigue, intracellular acidosis during handgrip exercise was attenuated by prolonged submaximal exercise. Healthy human subjects (n = 6) performed 5-min bouts of maximal rhythmic handgrip (RHG) before (CONTROL) and after prolonged (60-min) handgrip exercise (ATTEN-EX) designed to attenuate lactic acidosis in active muscle by partially depleting muscle glycogen. Concentrations of free intracellular phosphocreatine ([PCr]), adenosine triphosphate ([ATP]), and orthophosphate ([P(i)]) and pH were measured by 31P nuclear magnetic resonance spectroscopy and used to calculate adenosine diphosphate [ADP], [H2PO4-], and [HPO4(2-)]. Handgrip force output was measured with a dynamometer, and fatigue was determined by loss of maximal contractile force. After ATTEN-EX, the normal exercise-induced muscle acidosis was reduced. At peak CONTROL RHG, pH fell to 6.3 +/- 0.1 (SE) and muscle fatigue was correlated with [PCr] (r = 0.83), [P(i)] (r = 0.82), and [H2PO4-] (r = 0.81); [ADP] was 22.0 +/- 5.7 mumol/kg. At peak RHG after ATTEN-EX, pH was 6.9 +/- 0.1 and [ADP] was 116.1 +/- 18.2 mumol/kg, although [PCr] and [P(i)] were not different from CONTROL RHG (P greater than 0.05). After ATTEN-EX, fatigue correlated most closely with [ADP] (r = 0.84). The data indicate that skeletal muscle fatigue 1) is multifactorial, 2) can occur without decreased pH or increased [H2PO4-], and 3) is correlated with [ADP] after exercise-induced glycogen depletion.

Topics: Acidosis, Lactic; Adenosine Diphosphate; Adenosine Triphosphate; Adult; Exercise; Female; Glycogen; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Muscles; Phosphocreatine

The protective effects of atropine, diacetylmonoxime (DAM), and diazepam separately and in combination were investigated in rats exposed to malathion. Malathion (500 mg/kg, ip) inhibited acetylcholinesterase (AchE) activity in RBC and brain and produced hyperglycemia and hyperlactacidemia with depletion of glycogen in liver, triceps, and brain of animals 2 hr after its administration. Atropine (20 mg/kg, ip) given immediately after malathion abolished hyperglycemia and glycogenolytic effect but exhibited no effect on the recovery of inhibited AchE activity. DAM (100 mg/kg ip) given immediately after malathion significantly reactivated the inhibited AchE activity both in RBC and brain. It also partially modified hyperglycemia and glycogenolytic effect. Diazepam (50 mg/kg, ip) slightly modified AchE and abolished hyperglycemia, hyperlactacidemia, and glycogenolytic effects. A combination of these drugs protected the animals from the acute toxic effects of malathion.

Topics: Acidosis, Lactic; Animals; Atropine; Brain; Butanones; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diacetyl; Diazepam; Drug Therapy, Combination; Erythrocytes; Glycogen; Hyperglycemia; Liver Glycogen; Malathion; Male; Rats

Serum lactic acidosis is characterized by a pH less than 7.25 and lactate greater than 5 mEq. Although sodium bicarbonate (NaHCO3) is standard treatment for this condition, clinical and experimental studies suggest that high doses of NaHCO3 may be ineffectual or even detrimental to brain, cardiovascular, and respiratory function, as well as survival. For this reason, low dose therapy with NaHCO3 has been recommended. Sodium dichloroacetate (NaDCA) has been used successfully to treat clinical and experimentally-induced lactic acidosis. The present study was designed to compare the effects of low dose NaHCO3 with NaDCA on blood pressure, blood chemistries and brain metabolites in rats with a low flow-induced (Type A, the most common type) lactic acidosis. Fasted male Wistar rats were subjected to cerebral ischemia and systemic hypotension for 30 min at which time, if the pH or HCO-3 fell to 7.2 or 10, respectively, the rat was treated with NaHCO3, NaDCA, or an equal volume of sterile water. Over the 30 min of recirculation that followed ischemia, treatment had no effect on blood pressure or glucose or on brain glucose or glycogen. NaHCO3 had no effect on lactate but appeared to stabilize pH and increase HCO3- more than in sham- or NaDCA-treated rats. Although NaDCA caused a greater increase in HCO3- than sham treatment, pH continued to decline. However, lactate decreased more in NaDCA- than in sham- or NaHCO3- treated rats. These results suggest that low dose NaHCO3 is not detrimental in this model; however, although NaHCO3 stabilized pH, it did not rapidly correct the acidosis. NaDCA at this dose had no effect on the acidosis but was effective in decreasing lactate. Since serum lactate has previously correlated with survival and since higher doses of NaDCA have corrected lactic acidosis in other studies, future evaluation of postischemic treatment with higher doses of NaDCA is warranted.

Topics: Acetates; Acidosis, Lactic; Animals; Bicarbonates; Blood Glucose; Brain Chemistry; Brain Ischemia; Dichloroacetic Acid; Glycogen; Lactates; Male; Rats; Rats, Inbred Strains; Resuscitation; Sodium; Sodium Bicarbonate

Diazinon, in acute doses (40 mg/kg, i.p.) in rats produced tremors and convulsions with lactic acidosis which was accompanied by depletion of glycogen and activation of glycogen phosphorylase activity in triceps and diaphragm muscles, 2 h after its administration. Prevention of convulsions with phenobarbitone administered immediately before diazinon, resulted in neither the development of lactic acidosis nor mobilization of muscle glycogen or activation of glycogen phosphorylase. Lactic acidosis was due to depletion of glycogen through enhanced activity of glycogen phosphorylase in muscles on account of tremors and convulsions induced by diazinon in rats.

Topics: Acidosis, Lactic; Acute Disease; Animals; Diazinon; Female; Glycogen; Insecticides; Lactates; Lactic Acid; Muscles; Phosphorylases; Rats; Rats, Inbred Strains; Seizures

Topics: Acidosis; Acidosis, Lactic; Blood Chemical Analysis; Carbohydrate Metabolism; Diabetes Mellitus; Glycogen; Humans; Lactates; Metabolism