Summary
Recent studies have identified a group of patients with cytochrome oxidase (COX) deficiency presenting in infancy associated with a deficiency of mtDNA in muscle or other affected tissue (Moraes et al 1991). We used a novel approach to compare the level of mitochondrial (mtDNA) compared to nuclear DNA in skeletal muscle from a group of patients and controls, based on dot blots that were hybridized with a mtDNA probe labelled with35S[dCTP] and a reference nuclear DNA probe labelled with [32P]dCTP.
The ratio of mtDNA to nuclear DNA varied in samples from different muscles of the same individual. Secondly, fetal muscle had very low levels of mtDNA compared to nuclear DNA, and data from older controls (cross-sectional rather than sequential) suggest that this increases rapidly over the first 3 months after birth and thereafter more slowly. Four patients with COX deficiency had levels of mtDNA that were below the age-specific range defined by ‘normal’ quadriceps muscle. The clinical features of two of these patients were similar to earlier case reports of mtDNA depletion. In three patients the clinical course was relatively benign compared to cases that have previously been described.
Levels of mtDNA in skeletal muscle from some patients with other forms of muscle disease were also found to be low, suggesting that mtDNA depletion, possibly related to depletion of mitochondria, may be a relatively non-specific response of muscle to various pathological processes. However, there does appear to be a distinctive group of young patients with reduced cytochrome oxidase activity in muscle, in whom marked mtDNA depletion reflects the primary defect.
Similar content being viewed by others
References
Anderson S, Bankier AT, Barrell BG, et al (1981) Sequence and organisation of the human mitochondrial genome.Nature 290: 457–465.
Andreetta F, Tritschler HJ, Schon EA, DiMauro S, Bonilla E (1991) Localization of mitochondrial DNA in normal and pathological muscle using immunological probes: a new approach to the study of mitochondrial myopathies.Neurol Sci 105: 88–92.
Argov R, Gardner-Medwin D, Johnson M, Mastaglia F (1980) Congenital myotonic dystrophy.Arch Neurol 37: 693–696.
Church GM, Gilbert W (1984) Genomic sequencing.Proc Natl Acad Sci USA 81: 1991–1995.
Clayton DA (1991) Replication and transcription of vertebrate mitochondrial DNA.Annu Rev Cell Biol 7: 453–78.
Dallman P (1966) Cytochrome c in normal and hypertrophied heart.Nature 212: 608–609.
Dubowitz V, Brooke M.Muscle Biopsy: A Modern Approach. Philadelphia: Saunders, 1973.
Ekeren G, Sengers R, Stadhouders A (1992) Changes in volume densities and distribution of mitochondria in rat skeletal muscle after chronic hypoxia.Int J Exp Pathol 73: 51–60.
Erickson J, Rushford C, Dorney D, Wilson G, Schmickel R (1981) Structure and variation of human ribosomal DNA: molecular analysis of cloned fragments.Gene 16: 1–9.
Figarella-Branger D, Pellissier JF, Scheiner C, Wernert F, Desnuelle C (1992) Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac involvement.J Neurol Sci 108: 105–113.
Goto Y-I, Nonaka I, Horai S (1990) A mutation in the tRNA leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature 348: 651–653.
Holt IJ, Miller DH, Harding AE (1989) Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy.J Med Genet 26: 739–743.
Laguens R, Gomez-Dumm C (1967) Deoxyribonucleic acid synthesis in the heart mitochondria after acute and exhaustive exercise.Experientia 24: 163–164.
Mazziotta M, Bertini E, Ricci E, et al (1992) Fatal infantile liver failure associated with mitochondrial DNA depletion.Journal of Pediatrics 121: 896–901.
Moraes CT, Shanske S, Tritschler HJ, et al (1991) mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.Am J Hum Genet 48: 492–501.
Moraes C, Ricci E, Arnaudo E, Bonilla E, DiMauro S, Schon E (1993) Quantitative defects of mitochondrial DNA. In DiMauro S, Wallace DC and eds.Mitochondrial DNA in Human Pathology. New York: Raven Press, 97–108.
Nazar K, Greenleaf JE, Philpott D, Pohoska E, Olszewska K, Kaciuba-Uscilko H (1993) Muscle mitochondrial density after exhaustive exercise in dogs: prolonged restricted activity and retraining.Aviat Space Environ Med 64: 306–313.
Pollak J (1975) The maturation of the inner membrane of fetal rat liver mitochondria.Biochem J 150: 477–488.
Potter C, Ramshaw A, Stickland J, Parums D, McGee J (1993) Quantification of specific mRNA by flatbed scintillation counting of dual-labelled dot blots.Biotechniques 11: 392–396.
Poulton J, Deadman ME, Gardiner RM (1989) Duplications of mitochondrial DNA in mitochondrial myopathy (see comments).Lancet 1: 236–240.
Poulton J, Morten K, Freeman-Emmerson C, et al (1994) Does deficiency of the human mitochondrial transcription factor-hmtTFA cause infantile mitochondrial myopathy with mtDNA depletion?Hum Mol Genet 3: 1763–1769.
Shoubridge EA, Karpati G, Hastings KEM (1990) Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease.Cell 62: 43–49.
Simonetti S, Chen X, DiMauro S, Schon EA (1992) Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR.Biochim Biophys Acta 1180: 113–122.
Telerman-Toppet N, Biarent D, Bouton JM et al (1992) Fatal cytochrome c oxidase-deficient myopathy of infancy associated with mtDNA depletion. Differential involvement of skeletal muscle and cultured fibroblasts.J Inher Metab dis 15: 323–326.
Tritschler H-J, Andreetta F, Moraes CT, et al (1992) Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.Neurology 42: 209–217.
Wallace DC (1990) Report of the committee on human mitochondrial DNA.Cytogenet Cell Genet 55: 395–405.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Poulton, J., Sewry, C., Potter, C.G. et al. Variation in mitochondrial DNA levels in muscle from normal controls. Is depletion of mtDNA in patients with mitochondrial myopathy a distinct clinical syndrome?. J Inherit Metab Dis 18, 4–20 (1995). https://doi.org/10.1007/BF00711367
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00711367