title: Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation.
abstract: 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.
authors.affiliation: Department of Medicine, McMaster University Medical Center, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. tarnopol@mcmaster.ca
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
authors.forename: Brian D
authors.initials: BD
authors.lastname: Roy
authors.forename: Kathy
authors.initials: K
authors.lastname: Chorneyko
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lowther
authors.forename: Donald R
authors.initials: DR
authors.lastname: Johns
authors.forename: Jagdeep K
authors.initials: JK
authors.lastname: Sandhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Marianna
authors.initials: M
authors.lastname: Sikorska
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D002470:Cell Survival; D003401:Creatine / Q000627:therapeutic use*; D045303:Cytochromes b / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005080:Exercise Test; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects* / Q000473:pathology; D008297:Male; D017240:Mitochondrial Myopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D010807:Physical Endurance; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013177:Sports
chemical_list: D004272:DNA, Mitochondrial; D005609:Free Radicals; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D000255:Adenosine Triphosphate; D045303:Cytochromes b; D003401:Creatine