Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy
ABSTRACT 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.
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- "Of particular relevance to the decreased PCr levels and mitochondrial dysfunction in METH users, several 31 P-MRS studies of individuals with primary mitochondrial disease have reported decreased PCr levels in the resting state of muscles (Argov et al., 1987; Arnold et al., 1985; Hoang et al., 1998) as well as in affected brain regions (Barbiroli et al., 1993, 1995). Importantly, when there was no clinical brain involvement in the mitochondrial disease, patients had normal PCr levels (Rango et al., 2001). "
ABSTRACT: BACKGROUND: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and β-nucleoside triphosphate (β-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter. METHODS: Study participants consisted of 51 METH (age=32.8±6.7) and 23 healthy comparison (age=31.1±7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored. RESULTS: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub-analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1±1.0g) of METH use than males (1.4±1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02). CONCLUSIONS: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels.Drug and alcohol dependence 10/2012; 129(1-2). DOI:10.1016/j.drugalcdep.2012.09.015 · 3.28 Impact Factor
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- "We can speculate that this might also be the case in s-IBM, where sarcolemmal damage due to the cell-mediated inflammatory process may result in increased basal ATP consumption. The high resting cytosolic pH, present in Duchenne/Becker muscular dystrophy and s-IBM, but only occasionally reported in mitochondrial myopathies (Arnold et al., 1985; Matthews et al., 1991; Taylor et al., 1994; Lodi et al., 1997c), is a clear index of abnormal ionic regulation, and in Duchenne/Becker muscular dystrophy it has been interpreted as a consequence of an increase in the Na ϩ /H ϩ antiport set point due to high sarcoplasmic [Ca 2ϩ ] (Frelin et al., 1988). It can be seen from the data in Table 2 that the calculated free [ADP] in resting muscle is high, especially for the Fig. 3 Maximum rate of mitochondrial ATP production (V max ) as a function of the Calf Muscle Score (obtained adding the scores from the lateral and medial gastrocnemius, and the soleus muscles, see Patients and methods section) in s-IBM patients. "
ABSTRACT: Sporadic inclusion body myositis (s-IBM) is a chronic inflammatory myopathy of unknown pathogenesis. The common findings of ragged red fibres, cytochrome c oxidase-negative fibres and multiple mitochondrial DNA deletions in the muscle of patients with s-IBM have suggested that a deficit of energy metabolism may be of pathogenic relevance. To test this hypothesis we used 31P magnetic resonance spectroscopy to assess in vivo skeletal muscle mitochondrial function in the calf muscles of 12 patients with definite s-IBM. Eleven patients showed multiple mitochondrial DNA deletions in skeletal muscle and 67% showed ragged red fibres and/or cytochrome c oxidase-negative fibres. T1-weighted MR images showed increased signal intensity in the calf muscle of all patients except one. The involvement of calf muscle was confirmed by 31P magnetic resonance spectroscopy of resting muscle, which disclosed abnormalities in metabolite ratios in all patients. However, muscle oxidative metabolism assessed during recovery from exercise was normal in patients with s-IBM, as maximum rates of mitochondrial ATP production and post-exercise ADP recovery rates were within the normal range in all cases. We conclude that muscle mitochondrial abnormalities are a secondary process and unlikely to play a significant role in the pathogenesis of s-IBM.Brain 12/1998; 121 ( Pt 11):2119-26. DOI:10.1093/brain/121.11.2119 · 10.23 Impact Factor
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- "Analysis of PCr recovery therefore provides information about mitochondrial function. Recovery half-times of PCr and ADP were calculated from the semilogarithmic transformation of the first four data points in recovery (Arnold et al., 1985). "
ABSTRACT: We have used 31P magnetic resonance spectroscopy to investigate skeletal muscle bioenergetics in a total of 31 patients with myotonic dystrophy. Results from resting flexor digitorum superficialis and calf muscle showed a significant elevation in the concentration ratio of inorganic phosphate to ATP and a significant reduction in the phosphorylation potential. In addition, in resting calf muscle the concentration ratio of phosphocreatine to ATP was reduced, and the resting intracellular pH and calculated free cytosolic ADP concentration were elevated. In general, the abnormalities observed were more marked in those patients who were more severely affected as judged by their ability to exercise. During aerobic exercise in both calf muscle and flexor digitorum superficialis, phosphocreatine was depleted more rapidly in patients than in control subjects but the muscle acidified less and ADP concentrations were higher. Calculated ATP turnover was significantly elevated. Analysis of the recovery kinetics for phosphocreatine following exercise provides evidence for a small but significant reduction in mitochondrial function. Analysis of the response of flexor digitorum superficialis to ischaemic exercise provides evidence of a reduction in the relative utilization of glycogen to produce ATP which may account, in part, for the reduced acidification seen in exercising muscle in myotonic dystrophy. There was no definite evidence of an alteration in proton handling capacity in this condition.Brain 11/1997; 120 ( Pt 10):1699-711. DOI:10.1093/brain/120.10.1699 · 10.23 Impact Factor