Abstract
Neuromuscular disorders with defects in the mitochondrial ATP-generating system affect a large number of children and adults worldwide, but remain without treatment. We used a mouse model of mitochondrial myopathy, caused by a cytochrome c oxidase deficiency, to evaluate the effect of induced mitochondrial biogenesis on the course of the disease. Mitochondrial biogenesis was induced either by transgenic expression of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) in skeletal muscle or by administration of bezafibrate, a PPAR panagonist. Both strategies successfully stimulated residual respiratory capacity in muscle tissue. Mitochondrial proliferation resulted in an enhanced OXPHOS capacity per muscle mass. As a consequence, ATP levels were conserved resulting in a delayed onset of the myopathy and a markedly prolonged life span. Thus, induction of mitochondrial biogenesis through pharmacological or metabolic modulation of the PPAR/PGC-1alpha pathway promises to be an effective therapeutic approach for mitochondrial disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Bezafibrate / administration & dosage
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Cytochrome-c Oxidase Deficiency / drug therapy*
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Cytochrome-c Oxidase Deficiency / metabolism
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Disease Models, Animal
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Energy Metabolism / drug effects
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Energy Metabolism / genetics
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Female
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Mitochondria, Muscle / drug effects
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Mitochondria, Muscle / genetics
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Mitochondria, Muscle / metabolism*
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Mitochondrial Myopathies / drug therapy*
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Mitochondrial Myopathies / genetics*
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Mitochondrial Myopathies / pathology
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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PPAR gamma / agonists
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Phenotype
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Survival Rate
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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Transgenes
Substances
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Trans-Activators
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Transcription Factors
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Adenosine Triphosphate
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Bezafibrate