Journal of Neurology

, Volume 254, Issue 1, pp 29–37

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

  • Tina Dysgaard Jeppesen
  • Bjørn Quistorff
  • Flemming Wibrand
  • John Vissing


Clinical phenotypes of persons with mitochondrial DNA (mtDNA) mutations vary considerably. Therefore, diagnosing mitochondrial myopathy (MM) patients can be challenging and warrants diagnostic guidelines. 31phosphorous magnetic resonance spectroscopy (31P-MRS) have been included as a minor diagnostic criterion for MM but the diagnostic strength of this test has not been compared with that of other commonly used diagnostic procedures for MM. To investigate this, we studied seven patients with single, large-scale deletions-, nine with point mutations of mtDNA and 14 healthy subjects, who were investigated for the following: 1) 31P-MRS of lower arm and leg muscles before and after exercise, 2) resting and peak-exercise induced increases of plasma lactate, 3) muscle morphology and -mitochondrial enzyme activity, 4) maximal oxygen uptake (VO2max), 5) venous oxygen desaturation during handgrip exercise and 6) a neurological examination. All MM patients had clinical symptoms of MM, > 2% ragged red fibers in muscle, and impaired oxygen desaturation during handgrip. Fourteen of 16 patients had impaired VO2max, 10/16 had elevated resting plasma lactate, and 10/11 that were investigated had impaired citrate synthase-corrected complex I activity. Resting PCr/Pi ratio and leg Pi recovery were lower in MM patients vs. healthy subjects. PCr and ATP production after exercise were similar in patients and healthy subjects. Although the specificity for MM of some 31P-MRS variables was as high as 100%, the sensitivity was low (0–63%) and the diagnostic strength of 31P-MRS was inferior to the other diagnostic tests for MM. Thus, 31P-MRS should not be a routine test for MM, but may be an important research tool.


31-Phosphorous magnetic resonance spectroscopy muscle disorders mitochondrial myopathy diagnostic procedures mtDNA mutations 


  1. 1.
    Argov Z, Bank WJ, Maris J, Peterson P, Chance B (1987) Bioenergetic heterogeneity of human mitochondrial myopathies: phosphorus magnetic resonance spectroscopy study. Neurology 37:257–262PubMedGoogle Scholar
  2. 2.
    Argov Z, Bank WJ (1991) Phosphorus magnetic resonance spectroscopy (31P MRS) in neuromuscular disorders. Ann Neurol 30:90–97PubMedCrossRefGoogle Scholar
  3. 3.
    Argov Z, De Stefano N, Arnold DL (1996) ADP recovery after a brief ischemic exercise in normal and diseased human muscle–a 31P MRS study. NMR Biomed 9:165–172PubMedCrossRefGoogle Scholar
  4. 4.
    Arnold DL, Taylor DJ, Radda GK (1985) Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Ann Neurol 18:189–196PubMedCrossRefGoogle Scholar
  5. 5.
    Bangsbo J, Johansen L, Quistorff B, Saltin B (1993) NMR and analytical biochemical evaluation of PCr and nucleotides in the human calf muscle during contraction. J Appl Physiol 74:2034–2039PubMedGoogle Scholar
  6. 6.
    Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411PubMedGoogle Scholar
  7. 7.
    Chen JT, Taivassalo T, Argov Z, Arnold DL (2001) Modeling in vivo recovery of intracellular pH in muscle to provide a novel index of proton handling: application to the diagnosis of mitochondrial myopathy. Magn Reson Med 46:870–878PubMedCrossRefGoogle Scholar
  8. 8.
    Ciafaloni E, Ricci E, Shanske S, Moraes CT, Silvestri G, Hirano M, Simonetti S, Angelini C, Donati MA, Garcia C (1992) MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 31:391–398PubMedCrossRefGoogle Scholar
  9. 9.
    Dimauro S, Tay S, Mancuso M (2004) Mitochondrial encephalomyopathies: diagnostic approach. Ann N Y Acad Sci 1011:217–231PubMedCrossRefGoogle Scholar
  10. 10.
    Hoch JC, Stern AS (1995) NMR data processing. Wiley-Liss, New YorkGoogle Scholar
  11. 11.
    Janssen AJ, Smeitink JA, van den Heuvel LP (2003) Some practical aspects of providing a diagnostic service for respiratory chain defects. Ann Clin Biochem 40:3–8PubMedCrossRefGoogle Scholar
  12. 12.
    Jensen TD, Kazemi-Esfarjani P, Skomorowska E, Vissing J (2002) A forearm exercise screening test for mitochondrial myopathy. Neurology 58:1533–1538PubMedGoogle Scholar
  13. 13.
    Jeppesen TD, Olsen D, Vissing J (2003) Cycle ergometry is not a sensitive diagnostic test for mitochondrial myopathy. J Neurol 250:293–299PubMedCrossRefGoogle Scholar
  14. 14.
    Johnston W, Karpati G, Carpenter S, Arnold D, Shoubridge EA (1995) Late-onset mitochondrial myopathy. Ann Neurol 37:16–23PubMedCrossRefGoogle Scholar
  15. 15.
    Katz SD, Bleiberg B, Wexler J, Bhargava K, Steinberg JJ, LeJemtel TH (1993) Lactate turnover at rest and during submaximal exercise in patients with heart failure. J Appl Physiol 75:1974–1979PubMedGoogle Scholar
  16. 16.
    Kemp GJ, Taylor DJ, Thompson CH, Hands LJ, Rajagopalan B, Styles P, Radda GK (1993) Quantitative analysis by 31P magnetic resonance spectroscopy of abnormal mitochondrial oxidation in skeletal muscle during recovery from exercise. NMR Biomed 6:302–310PubMedGoogle Scholar
  17. 17.
    Krause KH, Bonjour JP, Berlit P, Kochen W (1985) Biotin status of epileptics. Ann N Y Acad Sci 447:297–313PubMedCrossRefGoogle Scholar
  18. 18.
    Krentz AJ, Coles NH, Williams AC, Nattrass M (1990) Abnormal regulation of intermediary metabolism after oral glucose ingestion in myotonic dystrophy. Metabolism 39:938–942PubMedCrossRefGoogle Scholar
  19. 19.
    Kuhl CK, Layer G, Traber F, Zierz S, Block W, Reiser M (1994) Mitochondrial encephalomyopathy: correlation of P-31 exercise MR spectroscopy with clinical findings. Radiology 192:223–230PubMedGoogle Scholar
  20. 20.
    Laguno M, Milinkovic A, de Lazzari E, Murillas J, Martinez E, Blanco JL, Lonca M, Biglia A, Leon A, Garcia M, Larrousse M, Garcia F, Miro JM, Gatell JM, Mallolas J (2005) Incidence and risk factors for mitochondrial toxicity in treated HIV/HCV-coinfected patients. Antivir Ther 10:423–429PubMedGoogle Scholar
  21. 21.
    Larsen AI, Aarsland T, Kristiansen M, Haugland A, Dickstein K (2001) Assessing the effect of exercise training in men with heart failure; comparison of maximal, submaximal and endurance exercise protocols. Eur Heart J 22:684–692PubMedCrossRefGoogle Scholar
  22. 22.
    Larson-Meyer DE, Newcomer BR, Hunter GR, Hetherington HP, Weinsier RL (2000) 31P MRS measurement of mitochondrial function in skeletal muscle: reliability, force-level sensitivity and relation to whole body maximal oxygen uptake. NMR Biomed 13:14–27PubMedCrossRefGoogle Scholar
  23. 23.
    Mariotti C, Uziel G, Carrara F, Mora M, Prelle A, Tiranti V, DiDonato S, Zeviani M (1995) Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: a morphological, biochemical and molecular-genetic study. J Neurol 242:547–556PubMedCrossRefGoogle Scholar
  24. 24.
    Matthews PM, Allaire C, Shoubridge EA, Karpati G, Carpenter S, Arnold DL (1991) In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease. Neurology 41:114–120PubMedGoogle Scholar
  25. 25.
    Matthews PM, Berkovic SF, Shoubridge EA, Andermann F, Karpati G, Carpenter S, Arnold DL (1991) In vivo magnetic resonance spectroscopy of brain and muscle in a type of mitochondrial encephalomyopathy (MERRF). Ann Neurol 29:435–458PubMedCrossRefGoogle Scholar
  26. 26.
    McCully KK, Argov Z, Boden BP, Brown RL, Bank WJ, Chance B (1988) Detection of muscle injury in humans with 31-P magnetic resonance spectroscopy. Muscle Nerve 11:212–216PubMedCrossRefGoogle Scholar
  27. 27.
    Mizuno M, Secher NH, Quistorff B (1994) NMR spectroscopy, rsEMG, and histochemical fiber types of human wrist flexor muscles. J Appl Physiol 76:531–588PubMedGoogle Scholar
  28. 28.
    Nakagawa Y, Ratkevicius A, Mizuno M, Quistorff B (2005) ATP economy of force maintenance in human tibialis anterior muscle. Med Sci Sports Exerc 37:937–943PubMedGoogle Scholar
  29. 29.
    Park JH, Vansant JP, Kumar NG, Gibbs SJ, Curvin MS, Price RR, Partain CL, James AE Jr (1990) Dermatomyositis: Correlative MR imaging and P-31 MR spectroscopy for quantitative characterization of inflammatory disease. Radiology 177:473–479PubMedGoogle Scholar
  30. 30.
    Polagr J, Johnson MA, Weightman D, Appleton D (1973) Data on fibre size in thirty-six human muscles. An autopsy study. J Neurol Sci 19:307–318CrossRefGoogle Scholar
  31. 31.
    Quistorff B, Johansen L, Sahlin K (1993) Absence of phosphocreatine resynthesis in human calf muscle during ischemic recovery - glycolysis and glycogenolysis are regulated by factors other than pH, Pi, ADP and AMP during ischaemia. Biochem J 291:681–686PubMedGoogle Scholar
  32. 32.
    Ratkevicius A, Quistorff B (2002) Metabolic costs of force generation for constant-frequency and catchlike-inducing electrical stimulation in human tibialis anterior muscle. Muscle Nerve 25:419–426PubMedCrossRefGoogle Scholar
  33. 33.
    Schwartz M, Vissing J (2002) Paternal inheritance of mitochondrial DNA. N Engl J Med 347:576–580PubMedCrossRefGoogle Scholar
  34. 34.
    Tarnopolsky MA, Parise G (1999) Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 22:1228–1233PubMedCrossRefGoogle Scholar
  35. 35.
    Taylor DJ, Kemp GJ, Radda GK (1994) Bioenergetics of skeletal muscle in mitochondrial myopathy. J Neurol Sci 127:198–206PubMedCrossRefGoogle Scholar
  36. 36.
    Vissing J (2002) Mitochondrial myopathies. In: Preedy VR, Peters TJ (eds) Skeletal Muscle: Pathology, Diagnosis and Management of Disease. Chapter 14 London, Greenwich Medical Media Ltd. pp 153–166Google Scholar
  37. 37.
    Vissing J, Salamon MB, Arlien-Soborg P, Norby S, Manta P, DiMauro S, Schmalbruch H (1998) A new mitochondrial tRNA(Met) gene mutation in a patient with dystrophic muscle and exercise intolerance. Neurology 50:1875–1878PubMedGoogle Scholar
  38. 38.
    Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM, Hopkins LC (1988) Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55:601–610PubMedCrossRefGoogle Scholar
  39. 39.
    Walker UA, Collins S, Byrne E (1996) Respiratory chain encephalomyopathies: A diagnostic classification. Eur Neurol 36:260–267PubMedGoogle Scholar
  40. 40.
    Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J (2001) Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. Ann Neurol 50:540–543PubMedCrossRefGoogle Scholar
  41. 41.
    Younkin DP, Berman P, Sladky J, Chee C, Bank W, Chance B (1987) 31P NMR studies in Duchenne muscular dystrophy: age-related metabolic changes. Neurology 37:165–169PubMedGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2007

Authors and Affiliations

  • Tina Dysgaard Jeppesen
    • 1
  • Bjørn Quistorff
    • 2
  • Flemming Wibrand
    • 3
  • John Vissing
    • 1
  1. 1.Neuromuscular Research Unit, Section 7611National University HospitalCopenhagenDenmark
  2. 2.NMR Center, The Panum InstituteUniversity of CopenhagenCopenhagenDenmark
  3. 3.John F. Kennedy InstituteGlostrupDenmark

Personalised recommendations