31P-MRS of skeletal muscle is not a sensitive diagnostic test for mitochondrial myopathy

Jeppesen, Tina Dysgaard; Quistorff, Bjørn; Wibrand, Flemming; Vissing, John

doi:10.1007/s00415-006-0229-5

Cited by 35 publications

(23 citation statements)

References 38 publications

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“…31 P-MRS also has detected low PCr in brain of individuals with RCD (21,23). Although 31 P-MRS offers direct and noninvasive measurement of the cellular energetic state, it is not in routine clinical use because it is technically difficult to perform, inaccessible to most clinical centers, and lacks diagnostic sensitivity for RCD (24). In the current study, we demonstrate a correlation between extracellular Cr levels and intracellular PCr depletion in RC-inhibited myotubes (Fig.…”

Section: Discussionsupporting

confidence: 53%

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

Shaham

Slate

Goldberger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

123

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Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle . These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine:creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases.biochemical genetics | biomarker | metabolomics | mitochondria T he respiratory chain (RC) of mammalian cells comprises a series of five enzymatic complexes embedded in the inner mitochondrial membrane and serves as the machinery for oxidative phosphorylation. Changes in RC activity influence key parameters such as the cellular energy charge and the NADH/ NAD + ratio and can impact the numerous metabolic pathways coupled to the RC directly or indirectly. In humans, inherited defects in mitochondrial (mt) or nuclear genes that encode RC proteins or factors necessary for its maturation and assembly lead to respiratory chain disease (RCD) (1). It is estimated that RCD affects at least 18.4 in 100,000 people (2) and represents the most common group of inborn errors of metabolism (3).The clinical presentation of RCD is highly variable in severity, age of onset, and the combination of organ systems involved, and the factors contributing to this variability are poorly understood (1). Consequently, the diagnosis can be challenging, and there are very limited means of objectively monitoring disease progression. A number of diagnostic algorithms have been proposed (4-6) that integrate clinical, biochemical, histological, and molecular findings. Abnormal concentrations of several metabolites in biological fluids, including the elevation of lactate, alanine, pyruvate, and the lac...

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Section: Discussionsupporting

confidence: 53%

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

Shaham

Slate

Goldberger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

123

View full text Add to dashboard Cite

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“…Similar to structural and lactate measures discussed earlier, the diagnostic sensitivity of 31 P is limited as it only assesses the output of the ETC in the tissue sampled [Jeppesen et al, 2007]. As few centers have phosphorus capabilities, more widespread data comparing the concordance of lactate and phosphorus metabolites will be helpful to evaluate the utility of this technology for serial monitoring and diagnostic specificity.…”

Section: P Measures: Phosphocreatine and Atpmentioning

confidence: 96%

The use of neuroimaging in the diagnosis of mitochondrial disease

Friedman

Shaw

Ishak

et al. 2010

Dev Disabil Res Revs

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Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

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“…Moreover, C(a-v)O 2 was not measured and impaired O 2 extraction could only be inferred from noninvasive data. Finally, genetic studies were not performed and we were unable to correlate the physiological abnormalities with mtDNA mutation load on skeletal muscle or the qualitative distribution of type fibers (39).…”

Section: Study Limitationsmentioning

confidence: 97%

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

Gimenes¹,

Neder²,

Corso³

et al. 2011

Braz J Med Biol Res

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31P-MRS of skeletal muscle is not a sensitive diagnostic test for mitochondrial myopathy

Cited by 35 publications

References 38 publications

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

The use of neuroimaging in the diagnosis of mitochondrial disease

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

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