Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation

Muscle Nerve. 2004 Apr;29(4):537-47. doi: 10.1002/mus.20020.


Mitochondrial cytopathies are associated with increased free radical generation and paracrystalline inclusions. Paracrystalline inclusions were serendipitously found in a young male athlete with a very high respiratory exchange ratio during steady-state exercise; he also had an unusually low aerobic capacity. Direct sequencing of the mitochondrial DNA (mtDNA) coding regions revealed a novel missense mutation (G15497A) resulting in a glycine-->serine conversion at a highly conserved site in the cytochrome b gene in the subject, his mother, and sister. Cybrids, prepared by fusion of the subject's platelets with either U87MG rho degrees or SH-SY5Y rho degrees cells, generated higher basal levels of reactive oxygen species (ROS), had a lower adenosine triphosphate (ATP) content, and were more sensitive to oxygen and glucose deprivation and peroxynitrite generation compared to control cybrids with wild-type mtDNA. Cell survival was significantly enhanced with 50 mmol/L creatine monohydrate (CM) administration. The subject was also treated with CM (10 g/d) for a period of 5 weeks and a repeat muscle biopsy showed no paracrystalline inclusions. The results suggest that the development of exercise-induced paracrystalline inclusions may be influenced by the G15497A mtDNA mutation, and that CM mitigates against the pathological consequences of this mutation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adult
  • Cell Survival
  • Creatine / therapeutic use*
  • Cytochromes b / genetics*
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Exercise Test
  • Free Radicals / metabolism*
  • Humans
  • Inclusion Bodies / drug effects*
  • Inclusion Bodies / pathology
  • Male
  • Mitochondrial Myopathies / drug therapy*
  • Mitochondrial Myopathies / genetics
  • Mitochondrial Myopathies / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Mutation / physiology*
  • Peroxynitrous Acid / metabolism
  • Physical Endurance
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sports


  • DNA, Mitochondrial
  • Free Radicals
  • Reactive Oxygen Species
  • Peroxynitrous Acid
  • Adenosine Triphosphate
  • Cytochromes b
  • Creatine