Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 27-yr-old woman with lifelong severe exercise intolerance manifested by muscle fatigue, lactic acidosis, and prominent symptoms of dyspnea and tachycardia induced by trivial exercise was found to have a skeletal muscle respiratory chain defect characterized by low levels of reducible cytochromes a + a3 and b in muscle mitochondria and marked deficiency of cytochrome c oxidase (complex IV) as assessed biochemically and immunologically. Investigation of the pathophysiology of the exercise response in the patient revealed low maximal oxygen uptake (1/3 that of normal sedentary women) in cycle exercise and impaired muscle oxygen extraction as indicated by profoundly low maximal systemic arteriovenous oxygen difference (5.8 ml/dl; controls = 15.4 +/- 1.4, mean +/- SD). The increases in cardiac output and ventilation during exercise, normally closely coupled to muscle metabolic rate, were markedly exaggerated (more than two- to threefold normal) relative to oxygen uptake and carbon dioxide production accounting for prominent tachycardia and dyspnea at low workloads. Symptoms in our patient are similar to those reported in other human skeletal muscle respiratory chain defects involving complexes I and III, and the exaggerated circulatory response resembles that seen during experimental inhibition of the mitochondrial respiratory chain. These results suggest that impaired oxidative phosphorylation in working muscle disrupts the normal regulation of cardiac output and ventilation relative to muscle metabolic rate in exercise.
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PMID:Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. 254 23

Five goat latissimus dorsi muscles (LDM) were submitted to a progressive chronic electrostimulation program to reach an integrated understanding of the fast-to-slow transformation process in large mammals. LDM were regularly sampled and followed during a period of 8 months. Each sample was simultaneously assessed for histoenzymological study, myosin and LDH isoforms and bioenergetic capacities [NADH dehydrogenase cytochrome c oxidoreductase (NADH Cyt c OR), succinate dehydrogenase cytochrome c oxidoreductase (Succ Cyt c OR), cytochrome c oxidase (Cyt c Ox) and LDH]. Such muscles were also tested with and without completion of II to I transformation for their mechanical properties in isometric and isotonic strain gauge testing. The conversion of fast-to-slow myosin monitored by heavy chain (HC I) and light chain slow component (LC2s) began a few days after stimulation and was almost 100% after 100 days. The H-LDH isoforms evolved similarly but did not reach 100% conversion after 200 days. The activity of respiratory chain oxidases increased within 36 h but to a variable extent and peaked after 32 days, corresponding to a 75% transformation of myosin compared to initial levels. NADH Cyt c OR, Succ Cyt c OR, and Cyt c Ox, respectively increased 10-, 5- and 5-fold. These activities then significantly decreased before the completion of the myofibrillar transformation and reached a plateau with stable activities that remained 2- to 3-fold higher than the unstimulated LDM. LDH activity sharply decreased until day 62 (5-fold) and then plateaued. Functionally, muscle showed a reduced speed of contraction and moderate reduction in power output but had become fatigue-resistant. This study documents the transformation process in large mammals and suggests the dynamic relation between workload, aerobic-anaerobic metabolism and the contractile myofibrillar system.
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PMID:Type II to type I transformation of chronically stimulated goat latissimus dorsi muscle: a histoenzymological, biochemical, bioenergetic, and functional study. 883 65

Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.
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PMID:Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. 915 50

Zidovudine (AZT) and didanosine (ddI), two drugs used in the treatment of AIDS, are also known to cause mitochondrial abnormalities. We investigated the physiological relevance of the mitochondrial defects by measuring in situ skeletal muscle performance and cytochrome c oxidase (CYTOX) enzyme activity in heart muscle, red highoxidative (RG) and white low-oxidative (WG) portions of the gastrocnemius muscle of control (n = 17), AZT-(n = 14), or ddI-treated (n = 11) rats for 28 days. We also evaluated the hypothesis that AZT treatment could alter the expression of the mitochondrial transcription factor A (mtTFA), a key molecule involved in mitochondrial DNA (mtDNA) replication and transcription. AZT had a pronounced effect on blood pressure and skeletal muscle performance, which were significantly decreased during contractile activity at 2 and 5 Hz, compared with control. A significant decrease in CYTOX activity in heart and RG, but not WG muscles, was also evident. In the heart, this was accompanied by an apparent compensatory increase in mtTFA mRNA level that could not be attributed to enhanced transcriptional activation mediated by nuclear respiratory factor 1 (NRF-1). In contrast with AZT, no effect of ddI was found on the extent of fatigue or muscle enzyme activity. These results indicate that AZT induces mitochondrial defects primarily in muscles with the highest oxidative capacities (heart and RG). The long-term effects of AZT on mitochondrial biogenesis have the potential to reduce muscle performance, but the effects on performance in this short-term study were likely due to an inability of the AZT-treated animals to maintain blood pressure during contractile activity.
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PMID:Zidovudine (AZT) induced alterations in mitochondrial biogenesis in rat striated muscles. 1053 63

The soluble Ca2+-binding protein parvalbumin (PV) is expressed at high levels in fast-twitch muscles of mice. Deficiency of PV in knockout mice (PV -/-) slows down the speed of twitch relaxation, while maximum force generated during tetanic contraction is unaltered. We observed that PV-deficient fast-twitch muscles were significantly more resistant to fatigue than were the wild type. Thus components involved in Ca2+ homeostasis during the contraction-relaxation cycle were analyzed. No upregulation of another cytosolic Ca2+-binding protein was found. Mitochondria are thought to play a physiological role during muscle relaxation and were thus analyzed. The fractional volume of mitochondria in the fast-twitch muscle extensor digitorum longus (EDL) was almost doubled in PV -/- mice, and this was reflected in an increase of cytochrome c oxidase. A faster removal of intracellular Ca2+ concentration ([Ca2+]i) 200-700 ms after fast-twitch muscle stimulation observed in PV -/- muscles supports the role for mitochondria in late [Ca2+]i removal. The present results also show a significant increase of the density of capillaries in EDL muscles of PV -/- mice. Thus alterations in the dynamics of Ca2+ transients detected in fast-twitch muscles of PV -/- mice might be linked to the increase in mitochondria volume and capillary density, which contribute to the greater fatigue resistance of these muscles.
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PMID:Deficiency in parvalbumin increases fatigue resistance in fast-twitch muscle and upregulates mitochondria. 1140 33

Mitochondrial DNA (mtDNA) mutations associated with rhabdomyolysis are rare but have been described in sporadic cases with mutations in the cytochrome b and cytochrome c oxidase (COX) genes and in 3 cases with tRNALeu mutation. We report a novel heteroplasmic G6708A nonsense mutation in the mtDNA COI gene encoding COX subunit I in a 30-year-old woman with muscle weakness, pain, fatigue, and one episode of rhabdomyolysis. Histochemical examination of muscle biopsy specimens revealed reduced COX activity in the majority of the muscle fibers (approximately 90%) and frequent ragged red fibers. Biochemical analysis showed a marked and isolated COX deficiency. Analysis of DNA extracted from single fibers revealed higher levels of the mutation in COX-deficient fibers (> 95%) compared with COX-positive fibers (1%-80%). The mutation was not detected in a skin biopsy, cultured myoblasts, or blood leukocytes. Nor was it identified in blood leukocytes from the asymptomatic mother, indicating a de novo mutation that arose after germ layer differentiation. Western blot analysis and immunohistochemical staining revealed that reduced levels of COX subunit I were accompanied by reduced levels of other mtDNA encoded subunits, as well as nuclear DNA encoded subunit IV, supporting the concept that COX subunit I is essential for the assembly of complex IV in the respiratory chain.
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PMID:Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I. 1575 Dec 26

Transcription profiling of genes encoding components of the respiratory chain and the ATP synthesizing apparatus of Mycobacterium tuberculosis was conducted in vivo in the infected mouse lung, and in vitro in bacterial cultures subjected to gradual oxygen depletion and to nitric oxide treatment. Transcript levels changed dramatically as infection progressed from bacterial exponential multiplication (acute infection) to cessation of bacterial growth (chronic infection) in response to host immunity. The proton-pumping type-I NADH dehydrogenase and the aa3-type cytochrome c oxidase were strongly down-regulated. Concurrently, the less energy-efficient cytochrome bd oxidase was transiently up-regulated. The nitrate transporter NarK2 was also up-regulated, indicative of increased nitrate respiration. The reduced efficiency of the respiratory chain was accompanied by decreased expression of ATP synthesis genes. Thus, adaptation of M. tuberculosis to host immunity involves three successive respiratory states leading to decreased energy production. Decreased bacterial counts in mice infected with a cydC mutant (defective in the cytochrome bd oxidase-associated transporter) at the transition to chronic infection provided initial evidence that the bd oxidase pathway is required for M. tuberculosis adaptation to host immunity. In vitro, NO treatment and hypoxia caused a switch from transcription of type I to type II NADH dehydrogenase. Moreover, cytochrome bd oxidase expression increased, but cytochrome c oxidase expression decreased slightly (nitric oxide) or not at all (hypoxia). These specific differences in respiratory metabolism during M. tuberculosis growth arrest in vitro and in vivo will guide manipulation of in vitro conditions to model bacterial adaptation to host immunity.
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PMID:Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. 1622 31

We have previously shown that the observed immediate increase in nitric oxide (NO) plays a significant role in the control of the cerebral microcirculation following traumatic brain injury (TBI). However, a second consequence of increased NO production after TBI may be impaired mitochondrial function, due to the fact that NO is a well-known inhibitor of cytochrome c oxidase (CcO). CcO is a key enzyme of the mitochondrial oxidative phosphorylation (OxPhos) machinery, which creates cellular energy in the form of ATP. NO competes with oxygen at the heme a(3)-Cu(B) reaction center of CcO. We thus hypothesized that TBI triggers inhibition of CcO, which would in turn lead to a decreased energy production by OxPhos at a time of an elevated energy demand for tissue remodeling. Here we show that TBI as induced by an acceleration weight drop model of diffuse brain injury in rats leads to CcO inhibition and dramatically decreased ATP levels in brain cortex. CcO inhibition can be partially restored by application of iNOS antisense oligonucleotides prior to TBI, which leads to a normalization of ATP levels similar to the controls. We propose that a lack of energy after TBI caused by inhibition of CcO is an important aspect of trauma pathology.
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PMID:Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels. 1803 45

Thirty years after Peter Mitchell was awarded the Nobel Prize for the chemiosmotic hypothesis, which links the mitochondrial membrane potential generated by the proton pumps of the electron transport chain to ATP production by ATP synthase, the molecular players involved once again attract attention. This is so because medical research increasingly recognizes mitochondrial dysfunction as a major factor in the pathology of numerous human diseases, including diabetes, cancer, neurodegenerative diseases, and ischemia reperfusion injury. We propose a model linking mitochondrial oxidative phosphorylation (OxPhos) to human disease, through a lack of energy, excessive free radical production, or a combination of both. We discuss the regulation of OxPhos by cell signaling pathways as a main regulatory mechanism in higher organisms, which in turn determines the magnitude of the mitochondrial membrane potential: if too low, ATP production cannot meet demand, and if too high, free radicals are produced. This model is presented in light of the recently emerging understanding of mechanisms that regulate mammalian cytochrome c oxidase and its substrate cytochrome c as representative enzymes for the entire OxPhos system.
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PMID:Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. 1884 28

Noonan syndrome (NS) is an autosomal dominant disorder, and a main feature is congenital heart malformation. About 50% of cases are caused by gain-of-function mutations in the tyrosine phosphatase SHP2/PTPN11, a downstream regulator of ERK/MAPK. Recently it was reported that SHP2 also localizes to the mitochondrial intercristae/intermembrane space (IMS), but the role of SHP2 in mitochondria is unclear. The mitochondrial oxidative phosphorylation (OxPhos) system provides the vast majority of cellular energy and produces reactive oxygen species (ROS). Changes in ROS may interfere with organ development such as that observed in NS patients. Several phosphorylation sites have been found in OxPhos components including cytochrome c oxidase (CcO) and cytochrome c (Cytc), and we hypothesized that OxPhos complexes may be direct or indirect targets of SHP2. We analyzed mitochondrial function using mouse fibroblasts from wild-types, SHP2 knockdowns, and D61G SHP2 mutants leading to constitutively active SHP2, as found in NS patients. Levels of OxPhos complexes were similar except for CcO and Cytc, which were 37% and 28% reduced in the D61G cells. However, CcO activity was significantly increased, as we also found for two lymphoblast cell lines from NS patients with two independent mutations in PTPN11. D61G cells showed lower mitochondrial membrane potential and 30% lower ATP content compared to controls. ROS were significantly increased; aconitase activity, a marker for ROS-induced damage, was decreased; and catalase activity was increased in D61G cells. We propose that decreased energy levels and/or increased ROS may explain, at least in part, some of the clinical features in NS that overlap with children with mitochondrial disorders.
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PMID:A suggested role for mitochondria in Noonan syndrome. 1983 54


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