title: SCID mice containing muscle with human mitochondrial DNA mutations. An animal model for mitochondrial DNA defects.
abstract: Defects of the mitochondrial genome are important causes of disease. Despite major advances in our investigation of patients, there is no effective therapy. Progress in this area is limited by the absence of any animal models in which we can evaluate treatment. To develop such a model we have injected human myoblasts into the tibialis anterior of SCID mice after inducing necrosis. After injection of normal human myoblasts, regenerating fibers expressed human beta-spectrin, confirming they were derived from fusion of human myoblasts. The stability of the muscle fibers was inferred by demonstrating the formation of motor end plates on the regenerating fibers. In addition, we show the presence of human cytochrome c oxidase subunit II, which is encoded by the mitochondrial genome, in the regenerated fibers. After injection of human myoblasts containing either the A8344G or the T8993C heteroplasmic mitochondrial DNA mutations, human beta-spectrin positive fibers were found to contain the mutation at a similar level to the injected myoblasts. These studies highlight the potential value of this model for the study of mitochondrial DNA defects.
authors.affiliation: Department of Neurology, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: K M
authors.initials: KM
authors.lastname: Clark
authors.forename: D J
authors.initials: DJ
authors.lastname: Watt
authors.forename: R N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: M A
authors.initials: MA
authors.lastname: Johnson
authors.forename: J B
authors.initials: JB
authors.lastname: Relvas
authors.forename: J W
authors.initials: JW
authors.lastname: Taanman
authors.forename: D M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics; D002802:Cholinesterases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000276:immunology* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009336:Necrosis; D012150:Polymorphism, Restriction Fragment Length; D012038:Regeneration; D012174:Retinitis Pigmentosa / Q000235:genetics; D013049:Spectrin / Q000378:metabolism; D016378:Tissue Transplantation
chemical_list: D004272:DNA, Mitochondrial; D013049:Spectrin; D003576:Electron Transport Complex IV; D002802:Cholinesterases