Energy State Of Muscle Research Articles

Triacylglycerol infusion improves exercise endurance in patients with mitochondrial myopathy due to complex I deficiency

A high-fat diet has been recommended for the treatment of patients with mitochondrial myopathy due to complex I (NADH dehydrogenase) deficiency (CID). This study evaluated the effects of intravenous infusion of isoenergetic amounts of triacylglycerol or glucose on substrate oxidation, glycolytic carbohydrate metabolism, and exercise endurance time and energy state of muscle in CID patients. Four CID patients and 15 control subjects were infused with triacylglycerol (3.7 mg x kg(-1) x min(-1)) or glucose (10 mg x kg(-1) x min(-1)) during low-intensity leg exercise. Respiratory calorimetry was used to evaluate mitochondrial substrate oxidation. The concentration and rate of appearance of plasma lactate (from dilution of [1-(13)C]lactate) were used to evaluate glycolytic carbohydrate metabolism. (31)P magnetic resonance spectroscopy was used to determine ratios of phosphocreatine to inorganic o-phosphate in forearm muscle during exercise. In 3 patients, leg exercise endurance time was better during the triacylglycerol infusion than during the glucose infusion. In all 4 patients, whole-body oxygen consumption rates during exercise were higher during triacylglycerol infusion than during the glucose infusion. In 3 patients, the concentration and rate of appearance of plasma lactate were lower during triacylglycerol infusion than during the glucose infusion. Ratios of phosphocreatine to inorganic o-phosphate during exercise were not significantly different between the 2 infusion studies or between the patients and control subjects. Triacylglycerol infusion is associated with a greater oxidation of substrates, lower rates of appearance and concentrations of plasma lactate, and greater leg exercise endurance time in myopathic CID patients than is glucose infusion. The energy state of muscle during exercise, however, was not significantly different after infusion of triacylglycerol or glucose.

Triacylglycerol infusion does not improve hyperlactemia in resting patients with mitochondrial myopathy due to complex I deficiency

A high-fat diet has been recommended for correction of biochemical abnormalities and muscle energy state in patients with complex I (NADH dehydrogenase) deficiency (CID). This study evaluated the effects of intravenous infusion of isoenergetic amounts of triacylglycerol or glucose on substrate oxidation, glycolytic carbohydrate metabolism, and energy state in patients with CID. Four CID patients and 15 matched control subjects were infused with triacylglycerol (1.85 mg x kg(-1) x min(-1)) or glucose (5 mg x kg(-1) x min(-1)) while at rest. Respiratory calorimetry was used to evaluate mitochondrial substrate oxidation. Metabolism of glycolytic carbohydrate was determined on the basis of the rates of appearance and concentrations of plasma lactate from dilution of [1-(13)C]lactate measurements. In addition, high-energy phosphate metabolism was measured in forearm muscle by (31)P magnetic resonance spectroscopy. Whole-body oxygen consumption rates were higher in the patients than in the control subjects (P < 0.05). Oxygen consumption and high-energy phosphate metabolism in forearm muscle were not significantly different between the 2 infusion groups. The rates of appearance and concentrations of plasma lactate were higher in each of the 4 patients than in the control subjects (P < 0.05) and were lower during the triacylglycerol infusion than during the glucose infusion (P < 0.05); the differences were comparable in the patients and control subjects. We conclude that triacylglycerol infusion, relative to glucose infusion, does not improve the oxidation of substrates or the energy state of skeletal muscle and does not lower the rates of appearance and concentrations of plasma lactate to normal values in CID patients at rest.

Energy state, pH, and vasomotor tone during hypoxia in precontracted pulmonary and femoral arteries.

To assess effects of smooth muscle energy state and intracellular pH (pH(i)) on pulmonary arterial tone during hypoxia, we measured ATP, phosphocreatine, P(i), and pH(i) by (31)P-NMR spectroscopy and isometric tension in phenylephrine-contracted rings of porcine proximal intrapulmonary arteries. Hypoxia caused early transient contraction followed by relaxation and late sustained contraction. Energy state and pH(i) decreased during relaxation and recovered toward control values during late contraction. Femoral arterial rings had higher energy state and lower pH(i) under baseline conditions and did not exhibit late contraction or recovery of energy state and pH(i) during hypoxia. In pulmonary arteries, glucose-free conditions abolished late hypoxic contraction and recovery of energy state and pH(i), but endothelial denudation abolished only late hypoxic contraction. NaCN had little effect at 0. 1 and 1.0 mM but caused marked vasorelaxation and decreases in energy state and pH(i) at 10 mM. These results suggest that 1) regulation of tone, energy state, and pH(i) differed markedly in pulmonary and femoral arterial smooth muscle, 2) hypoxic relaxation was mediated by decreased energy state or pH(i) due to hypoxic inhibition of oxidative phosphorylation, 3) recovery of energy state and pH(i) in hypoxic pulmonary arteries was due to accelerated glycolysis mediated by mechanisms intrinsic to smooth muscle, and 4) late hypoxic contraction in pulmonary arteries was mediated by endothelial factors that required hypoxic recovery of energy state and pH(i) for transduction in smooth muscle or extracellular glucose for production and release by endothelium.

Adenine nucleotide synthesis in exercising and endurance-trained skeletal muscle

Strenuous exercise leads to increased efflux of purine nucleoside and base that should necessitate recovery of adenine nucleotides by either the de novo synthesis or salvage pathway. De novo synthesis of adenine nucleotide was measured in quiescent and contracting muscle of sedentary and exercise-trained rats using an isolated perfused hindquarter preparation. Synthesis rates were assessed by measuring the incorporation of [1-14C]glycine into adenine nucleotide in muscles of both resting and stimulated hindlimbs after 1 h of either low- or high-energy demand isometric contractions. In nonstimulated sedentary and trained muscles, rates of de novo synthesis were similar. The effect of muscle contractions on de novo synthesis varied among muscle fiber types. Contracting, nonfatigued fast-twitch muscle sections showed significant declines in de novo synthesis in both sedentary and trained groups. Rates in slow-twitch red fibers and fatigued fast-twitch white fiber sections were not different from rest. Supplementing the perfusate with 5 mM ribose caused de novo synthesis to rise three- to fourfold in each of the fiber sections. However, the response in synthesis rates due to exercise was similar with or without ribose supplementation. De novo synthesis does not increase during exercise but exhibits an unchanged or reduced rate depending on the expected energy balance within the cell. This would occur if the energy state of muscle exerts significant control over de novo synthesis of adenine nucleotide.

In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondria1 disease

We have investigated the sensitivity and specificity of a rapid phosphorus magnetic resonance spectroscopy (MRS) protocol for detecting metabolic abnormalities in vivo in skeletal muscle of patients with mitochondrial disease. We examined 17 patients with mitochondrial myopathies. Sixteen had only mild or minimal myopathic signs and symptoms. Phosphorus magnetic resonance spectra from the resting gastrocnemius muscles showed an abnormal intracellular energy state (marked by an increased intracellular inorganic phosphate concentration) in 14/17. In 3/17, this was associated with a decreased phosphocreatine concentration. We also studied 20 patients with other diseases of muscle (inflammatory myopathies, metabolic myopathies, muscular dystrophies, and myasthenia gravis) that can present with similar clinical features. Spectra showed increased intracellular inorganic phosphate concentrations in 6/20. All of these muscle diseases were associated with evidence of muscle fiber necrosis. Abnormalities in the muscle energy state in these cases may be due to secondary mitochondrial dysfunction. Except for cases of polymyositis and dermatomyositis, these 6 other myopathies could be readily distinguished from the mitochondrial myopathies on the basis of the clinical examination and blood tests. We conclude that phosphorus MRS of resting muscle is practical in a clinical setting and has a useful sensitivity and specificity for mitochondrial myopathies when used in conjunction with standard noninvasive tests.

ATP breakdown products in human skeletal muscle during prolonged exercise to exhaustion.

To study changes in muscle energy state during prolonged exercise, especially in relation to fatigue, muscle biopsies were obtained from seven healthy males working until exhaustion on a cycle ergometer at 68% (63-74%) of their maximal oxygen uptake. Biopsies were taken at rest, after 15 and 45 min of exercise and at exhaustion, and analysed for ATP, ADP, AMP, inosine monophosphate (IMP) and hypoxanthine content by high performance liquid chromatography (HPLC), and for creatine phosphate (CP), lactate and glycogen by enzymatic fluorometric techniques. Glycogen content at exhaustion was approximately 30% of the pre-exercise level. The CP content decreased steeply during the first 15 min of exercise (P less than 0.01) and continued to decrease during the rest of the exercise period (P less than 0.05). Pronounced increases in contents of IMP (64% P less than 0.001) and hypoxanthine (69%, P less than 0.05) were found when exhaustion was approaching. Furthermore, energy charge [EC; (ATP + 0.5 ADP)/(ATP + ADP + AMP)] was decreased at exhaustion (P less than 0.05). The increases in IMP and hypoxanthine which occurred when exhaustion was approaching during prolonged submaximal exercise together with the decrease in EC during this phase of exercise suggest a failure of the exercising skeletal muscle to regenerate ATP at exhaustion.

Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy.

Abnormal mitochondria are an increasingly recognized cause of neuromuscular disease. We have used phosphorus magnetic resonance spectroscopy to monitor noninvasively the metabolism of high-energy phosphates and the intracellular pH of human skeletal muscle in vivo in 12 patients with mitochondrial myopathy. At rest, an abnormality could be demonstrated in 11 of 12 patients. Ten patients had evidence of a reduced muscle energy state with at least one of the following abnormalities: low phosphorylation potential, low phosphocreatine concentration, high adenosine diphosphate concentration, or high inorganic phosphate concentration. Two patients had abnormal resting muscle intracellular pH. In some patients phosphocreatine concentration decreased to low values during exercise despite limited work output. This was not accompanied by particularly severe intracellular acidosis. Evidence of impaired rephosphorylation of adenosine diphosphate to adenosine triphosphate during recovery from exercise was found in approximately half the patients. Phosphorus magnetic resonance spectroscopy is useful in the noninvasive diagnosis of mitochondrial myopathies and in defining the pathophysiological basis of these disorders.

Biochemical alterations in the skeletal muscle of vitamin E deficient rats.

Rats were fed a vitamin E deficient diet for 5–10 weeks and the energy state of the hind leg muscle was examined. Both creatine phosphate and ATP were decreased by 64 and 22% of the control values, respectively, in the skeletal muscles of rats on the vitamin E deficient diet for 10 weeks, whereas ADP was increased by more than 100% without any significant changes in the level of AMP. The ratios ATP/ADP and ATP/AMP also declined markedly in the hind leg muscles of the rats on the vitamin E deficient diet for 10 weeks. The concentrations of NAD+ and NADPH decreased, whereas no significant changes in the levels of NADH and NADP+ were observed in the muscles of vitamin E deficient animals. Feeding a normal diet for 4 weeks to rats previously on the vitamin E deficient diet was found to restore the energy state of the muscle towards normal. Although no changes in the ultrastructure of the skeletal muscle were apparent, the levels of lactate and pyruvate as well as the lactate/pyruvate ratio were increased in vitamin E deficiency. The activities of lactate dehydrogenase and malate dehydrogenase were decreased whereas α-glycerophosphate dehydrogenase activity did not change significantly. These results indicate a dramatic alteration in skeletal muscle metabolism of vitamin E deficient rats. It is suggested that such a change may partly be due to a defect in the process of energy production.