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)

Three siblings of a family affected with Leber's hereditary optic neuropathy (LHON) showed a mitochondrial DNA mutation at position 11778. The lactate response to a standardized effort was increased in only one case. Muscle biopsies and biochemistry of muscle and platelet mitochondrial enzymes were normal. All patients showed an altered energy metabolism during exercise and during recovery after exercise on phosphorus 31-magnetic resonance spectroscopy (31P-MRS) of muscle. Brain 31P-MRS showed a decreased energy reserve (decreased PCr/Pi ratio) in all patients. 31P-MRS noninvasively demonstrated an altered mitochondrial energy metabolism in muscle and, for the first time, in the brains of LHON patients.
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PMID:Leber's hereditary optic neuropathy: genetic, biochemical, and phosphorus magnetic resonance spectroscopy study in an Italian family. 186 7

The mechanism of muscle fatigue was studied by 31P-MRS. During tetanic contraction for 2 minutes(min), the tension measured with a strain gauge and Phosphocreatine(PCr)/Inorganic phosphate(Pi)+ Phosphomonoester(PME) ratio decreased to 31.5 +/- 4.4% of the control value and 0.6 +/- 0.1, respectively. The intracellular pH(pH) also decreased to 6.62 +/- 0.04. Toward the end of the stimulation, the tension decreased to 25.3 +/- 1.9% of the control value. However, during 20min stimulation, the PCr/(Pi+PME) ratio increased to 2.5 +/- 0.5 and the pH to 6.91 +/- 0.04. These results show that muscular fatigue is ascribable not to a decreased level of high energy metabolites required for actomyosin ATPase, but to an increase in the threshold intensity of excitation in excitation-contraction coupling.
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PMID:Observation of fatigue unrelated to gross energy reserve of skeletal muscle during tetanic contraction--an application of 31P-MRS. 319 34

To understand the mechanism of post-poliomyelitis muscular atrophy (PPMA) and the post-polio syndrome (PPS) in general, we performed the following studies: (1) histopathology in spinal cord sections from patients who died 9 days to 44 years after acute paralytic poliomyelitis; (2) enzyme histochemistry, immunocytochemistry (for lymphocyte subsets, MHC antigens and N-CAM) and polymerase chain reaction (PCR) for poliovirus RNA in the muscle biopsies from symptomatic or asymptomatic muscles of post-polio patients; (3) determination of lymphocyte subsets and circulating IgG or IgM antibodies against GM1 and poliovirus; (4) virological studies in the spinal fluid for oligoclonal bands and search for poliovirus genome with PCR; (5) electrophysiological studies including single fiber EMG, fiber density and macro-EMG; and (6) [31P] exercise MRS spectroscopy on previously affected muscles to search for a metabolic correlate of fatigue. These studies concluded that in PPS a continuing dysfunction is present in the spinal cord motor neurons, resulting in ongoing muscle denervation and reinnervation first evident at the axonal branch points. Symptoms are related to attrition of the oversprouting motor neurons which after a period of time cannot support all their axonal sprouts, resulting in failure of re-reinnervation. In some patients with PPS there is also an ongoing immune activation and presence of defective viral particles in the spinal fluid. However, their role in the pathogenesis of PPS is presently unknown.
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PMID:Pathogenetic mechanisms of post-polio syndrome: morphological, electrophysiological, virological, and immunological correlations. 761 26

The use of MRS has become more widespread as cost and availability have improved. It has been demonstrated that MRS of human skeletal muscle can play a significant role in (1) understanding healthy muscle metabolism and the mechanisms of muscle fatigue, (2) understanding the effects of disease on muscle metabolism and function, (3) monitoring the efficacy of therapeutic intervention, and (4) the confirmation of disease diagnoses. The results of the 31P MRS studies of disease are summarized in the Table 1. A few conditions (McArdle's, PFK deficiency) are associated with failure to develop acidosis during exercise. This response appears to be relatively specific to these metabolic myopathies. For most of the conditions reviewed here, however, the metabolic findings of reduced PCr/Pi and greater acidosis during exercise with impaired recovery of PCr/Pi and pH are very similar. The nonspecificity of the MRS results suggests the possibility that a common mechanism may be at work in all of these diseases. A major question to arise from clinical studies using MRS concerns the extent to which deconditioning may have played a role in some of these findings. This is because conditions associated with muscle weakness, rapid fatiguability, and muscle pain during or following vigorous physical activity may also be those that lead to deconditioning. In virtually all studies reviewed here, healthy, active subjects were used as controls. There are no examples in which controls were appropriately matched to the subjects for their level of conditioning. Conditioning could be assessed by questionnaire, activity logs, activity monitoring devices, or measurements of conditioning effects such as maximal oxygen consumption. The role of deconditioning in the decreased quality of life of persons with chronic diseases has not been fully explored. Future studies of chronic disease using MRS should combine MRS with other techniques to further probe the mechanisms of muscle metabolism under various conditions, and the extent to which these mechanisms are sensitive to the level of physical conditioning.
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PMID:Magnetic resonance spectroscopy studies of human muscle. 814 Feb 29

We studied changes in muscle proton (1H) transverse relaxation times (T2) by magnetic resonance imaging during exercise and compared these changes with alterations in muscle metabolism measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Eleven subjects completed two trials of intermittent incremental forearm wrist flexion exercise requiring 30 contractions/min for 5 min, 7 min of recovery between stages, and 5-N load increments/stage. Between stages of the first trial, T2 images of muscle 1H were obtained. Muscle T2 increased from 27.3 +/- 1.1 (SD) ms at rest to 35.8 +/- 3.6 ms after volitional fatigue (P < 0.05), whereas less active wrist extensor muscle T2 remained unchanged (26.8 +/- 0.9 to 28.8 +/- 1.6 ms; P > 0.05). After localizing the predominant muscle recruited from the T2 images, subjects completed an identical trial at least 1 wk later but involving surface coil 31P-MRS of the T2-enhanced muscle to measure the H+ concentration ([H+]). Intramuscular [H+] of T2-enhancing muscle increased from 1.1 +/- 0.1 x 10(-7) M at rest to 4.1 +/- 2.0 x 10(-7) M after volitional fatigue. Both muscle T2 and intramuscular [H+] increased in a bimodal manner, with T2 increasing before muscle [H+] (P < 0.05). The correlation coefficient between the percent change in T2 and muscle [H+] during exercise was +0.74 (range 0.48-0.98; P < 0.05) and +0.47 during recovery. After 12 min of recovery, muscle [H+] decreased to 1.4 +/- 0.3 x 10(-7) M (P < 0.05), and T2 remained close to postexercise values (32.2 +/- 3.1 ms, P > 0.05). The data indicate that 1) the T2 increases during increases in exercise intensity are nonlinear, 2) the T2 increases during exercise are significantly correlated with increases in [H+], and 3) the slow recovery of T2 compared with [H+] indicates that [H+] has a minor contribution to the recovery in T2.
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PMID:Changes in muscle proton transverse relaxation times and acidosis during exercise and recovery. 856 85

In recent years, a number of 31phosphorus magnetic resonance spectroscopy (P-MRS) studies on the frontal lobe of schizophrenics have been performed, reporting alterations of phospholipids and high-energy phosphates. Deicken et al. (1994b) recently found positive correlations between left frontal phosphomonoester% (PME%) levels and the performance of a specific frontal lobe task, the Wisconsin Card Sorting Test (WCST), in schizophrenics. In the present paper, the correlations between phospholipids and high-energy phosphates in the frontal lobe of 26 schizophrenics and 23 controls measured with a volume-selective P-MRS method were investigated. Overall, we could not find any correlations between WCST results and phospholipid levels, but in controls phosphocreatine% (PCr%) and PCr/adenenosine triphosphate (ATP) ratios were negatively correlated with test performance. Since PCr behaves as a buffer of ATP, in the sense that when ATP is consumed by neuronal activity PCr is catalysed rapidly to ATP, increased PCr% values and, moreover, increased PCr/ATP ratios point to a decreased ATP consumption. Thus, the correlations found between PCr% and PCr/ATP and test performance in controls point to an association between reduced performance in a specific frontal lobe task and decreased energy demanding processes at rest. This association was not found in schizophrenics, possibly due to the influence of neuroleptic medication or the disease process per se.
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PMID:High-energy phosphates in the frontal lobe correlate with Wisconsin Card Sort Test performance in controls, not in schizophrenics: a 31phosphorus magnetic resonance spectroscopic and neuropsychological investigation. 963 35

1. The main purpose of this study was to evaluate non-invasively with magnetic resonance spectroscopy (1H-MRS) changes in the concentrations of intracellular (IT) and extracellular (between muscle fibres) triglycerides (ET) in skeletal muscles of trained males (age range: 24-38 years) during two standard exercise protocols of alternating velocities. 2. Protocol 1 consisted of locomotion in a shuttle manner between two lines 30 m apart at four different velocities (1, 2, 3, and 4 m s-1) which were alternated every minute in a standard routine for 90 min, whereas Protocol 2 included locomotion between two lines 20 m apart at only three velocities (2, 2.7 and 4 m s-1) until volitional exhaustion. The heart rate during both protocols fluctuated between 140 and 200 beats min-1. 3. Using pre-exercise muscle water to quantify individual total creatine (TCr) that was utilized as an internal standard and assuming that TCr does not change during exercise, subjects' mean IT and ET concentrations in soleus (Sol) muscle before Protocol 1 (n = 8) were 45.8 +/- 4.8 mmol (kg dry weight)-1 (mean +/- S.E.M.) and 93.1 +/- 14.1 mmol (kg dry weight)-1, respectively. After the exercise, the concentrations of IT and ET were not significantly different from the values at rest. Before Protocol 2 (n = 4), IT concentrations in Sol, gastrocnemius (Gast) and tibialis (Tib) muscles were 46.4 +/- 13.6, 35.0 +/- 12.1 and 23.1 +/- 4.8 mmol (kg dry weight)-1, respectively, and were not affected by the exhaustive exercise. The ET concentrations in Sol, Gast and Tib were 136.4 +/- 38.1, 175.3 +/- 86.5 and 79.3 +/- 20.0 mmol (kg dry weight)-1 respectively, and they did not change significantly after exhaustion. 4. The study showed that levels of IT and ET were not affected by alternating intensity exercise to fatigue. This suggests that IT and ET in human Sol, Gast and Tib muscles do not contribute significantly to the energy turnover during this type of exercise. Energy for this type of muscle contraction may arise primarily from muscle phosphocreatine (PCr) and glycogen breakdown, circulating glucose and fatty acids from triglycerides other than those encountered within and between muscle cells.
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PMID:Intracellular and extracellular skeletal muscle triglyceride metabolism during alternating intensity exercise in humans. 970 8

Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.
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PMID:Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy. 1095 34

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
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PMID:Peripheral neuropathy and antiretroviral drugs. 1129 2

Magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (P-31 MRS) provide unique, quantitative data that cannot be obtained from routine laboratory tests. MRI is the method of choice for imaging of muscle abnormalities. It is also a very sensitive technique for localizing nonhomogeneous inflammation in inflammatory myopathies such as dermatomyositis, juvenile dermatomyositis, amyopathic dermatomyositis, polymyositis, and inclusion body myositis. During treatment of inflammatory myopathies, the extent and severity of inflammation may decrease at varying rates, but weakness and fatigue remain serious clinical problems. The metabolic abnormalities detected with P-31 MRS are more persistent and can be used for objective patient evaluation after the disappearance of inflammation and normalization of serum levels of muscle enzymes. With P-31 MRS, biochemical defects are quantitated, including low levels of ATP and phosphocreatine (PCr) and elevated concentrations of ADP and inorganic phosphate (Pi), which may all be related to weakness and fatigue. Thus, MRI and P-31 MRS are useful in assessing the status of patients with inflammatory myopathies during treatment with prednisone and immunosuppressive drugs.
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PMID:Utility of magnetic resonance imaging in the evaluation of patients with inflammatory myopathies. 1147 53


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