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Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and in mitochondrial biogenesis in skeletal muscle. PGC-1α regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1α in muscle cells results in increases in mitochondrial content. In this context, it has been proposed that the increase in PGC-1α protein expression mediates the exercise-induced increase in mitochondrial biogenesis. However, we found that mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1α protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1α mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1α in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1α into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1α protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, δ-aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1α may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1α protein sustains and enhances the increase in mitochondrial biogenesis. Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and in mitochondrial biogenesis in skeletal muscle. PGC-1α regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1α in muscle cells results in increases in mitochondrial content. In this context, it has been proposed that the increase in PGC-1α protein expression mediates the exercise-induced increase in mitochondrial biogenesis. However, we found that mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1α protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1α mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1α in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1α into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1α protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, δ-aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1α may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1α protein sustains and enhances the increase in mitochondrial biogenesis. Exercise is a powerful inducer of mitochondrial biogenesis in skeletal muscle (1Holloszy J.O. Booth F.W. Ann. Rev. Physiol. 1976; 38: 273-291Crossref PubMed Scopus (760) F.W. of Exercise and of biogenesis the expression of the mitochondrial and the nuclear that mitochondrial of nuclear and transcription that the mitochondrial proteins and of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) peroxisome proliferator-activated receptor γ nuclear respiratory factor nuclear respiratory factor cytochrome oxidase subunit δ-aminolevulinate p38 p38 protein transcription factor peroxisome proliferator-activated receptor γ nuclear respiratory factor nuclear respiratory factor cytochrome oxidase subunit δ-aminolevulinate p38 p38 protein transcription factor has increases in mitochondrial biogenesis and Rev. PubMed Scopus PubMed Scopus PubMed Scopus PGC-1α and the transcription that expression of nuclear mitochondrial proteins and that expression of mitochondrial transcription factor regulates mitochondrial the expression of mitochondrial proteins Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus of exercise or of muscle increases in PGC-1α and protein in skeletal muscle PubMed Scopus PubMed Scopus Physiol. Scopus J.O. PubMed Scopus Physiol. PubMed Scopus has been that the exercise-induced increase in PGC-1α expression mediates the increase in mitochondrial biogenesis PubMed Scopus PubMed Scopus Physiol. Scopus J.O. PubMed Scopus Physiol. PubMed Scopus PubMed Scopus However, we the of this adaptive we found that mitochondrial proteins with short increase in with the increase in PGC-1α protein. In this context, the of the to the that the initial phase of the exercise-induced adaptive increase in is activation, rather than increased expression, of that increases in the binding of to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 as as the increases in the mRNAs of cytochrome c, δ-aminolevulinate synthase and citrate synthase, the increase in PGC-1α protein support our of the of in the p38 MAPK and transcription factor of subunit the of and NRF-2 and receptor J.O. Physiol. PubMed Scopus a the and Exercise and a of and the of exercise mitochondrial biogenesis, a of the of Physiol. in the exercise into of the and and as J.O. PubMed with of and and of and of in to the of and This the of of in of with 1 1 and and and and to the a nuclear and in a of 1 1 and and 4 and of muscle as the of PubMed and the and as J.O. Physiol. PubMed Scopus J.O. 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PGC-1α protein increased with a increase the finding of increases in proteins that PGC-1α prior to an increase in PGC-1 protein that the initial adaptive increase in mitochondrial biogenesis is the exercise-induced increase in PGC-1α protein in mRNAs of the of PGC-1α in the phase of the to we citrate synthase, and cytochrome c mRNAs a of in the mRNAs citrate synthase, and cytochrome c increased this prior to the increase in PGC-1α synthase, citrate synthase and cytochrome c mRNAs increased in with in of p38 MAPK and has been that p38 MAPK and PGC-1α PubMed Scopus PubMed Scopus in of resulted in a increase in p38 MAPK also an increase in of the p38 MAPK transcription factor to the protein the PGC-1α promoter and PGC-1α transcription PubMed Scopus increases p38 MAPK and of with the into the has been that in PGC-1α is in the PubMed Scopus However, as in in resting skeletal most of the PGC-1α is in the cytosol. protein as a of the of of the nuclear with proteins protein to the of exercise the of in of the nuclear the also in the of resting and as in the nuclear protein of resulted in a increase in the of PGC-1α in the an increase in PGC-1α protein in the nucleus. of and PGC-1α in the nuclear of protein in the and nuclear as an of the of of the nuclear with protein. the of resting and as in of the nuclear protein in the nuclear most of the PGC-1α protein in skeletal muscle is in the cytosol. exercise-induced increases in PGC-1α in the nucleus. increase in PGC-1α protein in the in response to and NRF-2 and transcription that in mitochondrial biogenesis PubMed Scopus the that activation rather than increased expression of PGC-1α mediates the initial phase of exercise-induced mitochondrial biogenesis, we and NRF-2 the to binding of to the binding the cytochrome c promoter and binding of NRF-2 to an NRF-2 binding the cytochrome oxidase subunit in and NRF-2 binding increased in response to a of before an increase in PGC-1α protein binding to the cytochrome c promoter and NRF-2 binding to the promoter is increased in of with the transcription coactivator PGC-1α regulates the expression of the mitochondrial proteins that mediate and Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PGC-1α mediates this and transcription that expression of mitochondrial proteins PubMed Scopus PubMed Scopus PubMed Scopus of PGC-1α in muscle cells results in increases in mitochondria, with of the and PubMed Scopus PubMed Scopus overexpression of PGC-1α increases the mitochondrial of skeletal muscle and of muscle to muscle PubMed Scopus an in skeletal muscle that is to that PGC-1α with increases in the of the mitochondrial of the citrate J.O. PubMed Scopus mitochondrial respiratory J.O. Physiol. PubMed Scopus J.O. PubMed and the J.O. Physiol. PubMed Scopus J.O. PubMed Scopus and increases in the to and J.O. PubMed J.O. PubMed Scopus J.O. Physiol. PubMed Scopus and J.O. PubMed in mitochondrial biogenesis is the of the transcription that the mitochondrial and most the of Rev. 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PubMed Scopus PubMed Scopus However, an of the of the adaptive we of the mitochondrial proteins with short that PGC-1α to increase in with PGC-1α finding led to the that the initial phase of the adaptive increase in mitochondrial biogenesis exercise is activation of PGC-1α rather than the increase in PGC-1α protein results of the support this of is that the binding of the transcription factor to response the cytochrome c promoter and of NRF-2 to response the promoter increased in response to exercise prior to an increase in PGC-1α protein. and NRF-2 binding PGC-1α PubMed Scopus PubMed Scopus of that PGC-1α activation, rather than the increase in PGC-1α mediates the initial of mitochondrial biogenesis exercise is that the and protein of a of mitochondrial increased prior to the increase in PGC-1α our this is the that mitochondrial biogenesis increased activation of that PGC-1α regulates mitochondrial biogenesis has in PGC-1α of cells or increased overexpression or or in response to that increase mitochondrial biogenesis as or exercise Rev. 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Scopus PubMed Scopus of p38 MAPK increased and PGC-1α promoter in PubMed Scopus Furthermore, overexpression of the p38 in resulted in increased expression of PGC-1α PubMed Scopus PubMed Scopus that activation of p38 is to the adaptive increase in mitochondrial biogenesis of to and the protein the PGC-1α promoter and increased PGC-1α expression PubMed Scopus PubMed Scopus that exercise results in activation of p38 and of with and support this However, we hypothesize that the increase in PGC-1α protein expression the phase of this adaptive response and that the initial phase increased of mitochondrial proteins activation of this study, we found that most of the PGC-1α in resting skeletal muscle is in the and that exercise movement of PGC-1α into the nucleus. 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Physiol. 1976; 38: 273-291Crossref PubMed Scopus (760) F.W. of Exercise and of biogenesis the expression of the mitochondrial and the nuclear that mitochondrial of nuclear and transcription that the mitochondrial proteins and of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) peroxisome proliferator-activated receptor γ nuclear respiratory factor nuclear respiratory factor cytochrome oxidase subunit δ-aminolevulinate p38 p38 protein transcription factor peroxisome proliferator-activated receptor γ nuclear respiratory factor nuclear respiratory factor cytochrome oxidase subunit δ-aminolevulinate p38 p38 protein transcription factor has increases in mitochondrial biogenesis and Rev. PubMed Scopus PubMed Scopus PubMed Scopus PGC-1α and the transcription that expression of nuclear mitochondrial proteins and that expression of mitochondrial transcription factor regulates mitochondrial the expression of mitochondrial proteins Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus of exercise or of muscle increases in PGC-1α and protein in skeletal muscle PubMed Scopus PubMed Scopus Physiol. Scopus J.O. PubMed Scopus Physiol. PubMed Scopus has been that the exercise-induced increase in PGC-1α expression mediates the increase in mitochondrial biogenesis PubMed Scopus PubMed Scopus Physiol. Scopus J.O. PubMed Scopus Physiol. PubMed Scopus PubMed Scopus However, we the of this adaptive we found that mitochondrial proteins with short increase in with the increase in PGC-1α protein. In this context, the of the to the that the initial phase of the exercise-induced adaptive increase in is activation, rather than increased expression, of that increases in the binding of to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 as as the increases in the mRNAs of cytochrome c, δ-aminolevulinate synthase and citrate synthase, the increase in PGC-1α protein support our of the of in the p38 MAPK and transcription factor of subunit the of and NRF-2 and receptor J.O. Physiol. PubMed Scopus a the and Exercise and a of and the of exercise mitochondrial biogenesis, a of the of Physiol. in the exercise into of the and and as J.O. PubMed with of and and of and of in to the of and This the of of in of with 1 1 and and and and to the a nuclear and in a of 1 1 and and 4 and of muscle as the of PubMed and the and as J.O. Physiol. PubMed Scopus J.O. 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PGC-1α protein increased with a increase the finding of increases in proteins that PGC-1α prior to an increase in PGC-1 protein that the initial adaptive increase in mitochondrial biogenesis is the exercise-induced increase in PGC-1α protein in mRNAs of the of PGC-1α in the phase of the to we citrate synthase, and cytochrome c mRNAs a of in the mRNAs citrate synthase, and cytochrome c increased this prior to the increase in PGC-1α in of p38 MAPK and has been that p38 MAPK and PGC-1α PubMed Scopus PubMed Scopus in of resulted in a increase in p38 MAPK also an increase in of the p38 MAPK transcription factor to the protein the PGC-1α promoter and PGC-1α transcription PubMed Scopus increases p38 MAPK and of with the into the has been that in PGC-1α is in the PubMed Scopus However, as in in resting skeletal most of the PGC-1α is in the cytosol. protein as a of the of of the nuclear with proteins protein to the of exercise the of in of the nuclear the also in the of resting and as in the nuclear protein of resulted in a increase in the of PGC-1α in the an increase in PGC-1α protein in the nucleus. of and PGC-1α in the nuclear of protein in the and nuclear as an of the of of the nuclear with protein. the of resting and as in of the nuclear protein in the nuclear most of the PGC-1α protein in skeletal muscle is in the cytosol. exercise-induced increases in PGC-1α in the nucleus. increase in PGC-1α protein in the in response to and NRF-2 and transcription that in mitochondrial biogenesis PubMed Scopus the that activation rather than increased expression of PGC-1α mediates the initial phase of exercise-induced mitochondrial biogenesis, we and NRF-2 the to binding of to the binding the cytochrome c promoter and binding of NRF-2 to an NRF-2 binding the cytochrome oxidase subunit in and NRF-2 binding increased in response to a of before an increase in PGC-1α protein binding to the cytochrome c promoter and NRF-2 binding to the promoter is increased in of with the of in PGC-1α and the of a of and receptor proteins increased in muscle expression of is PGC-1α PubMed Scopus PubMed Scopus PubMed Scopus occurred before an increase in PGC-1α protein. PGC-1α protein increased with a increase the finding of increases in proteins that PGC-1α prior to an increase in PGC-1 protein that the initial adaptive increase in mitochondrial biogenesis is the exercise-induced increase in PGC-1α protein in mRNAs of the of PGC-1α in the phase of the to we citrate synthase, and cytochrome c mRNAs a of in the mRNAs citrate synthase, and cytochrome c increased this prior to the increase in PGC-1α protein. Exercise in of p38 MAPK and has been that p38 MAPK and PGC-1α PubMed Scopus PubMed Scopus in of resulted in a increase in p38 MAPK also an increase in of the p38 MAPK transcription factor to the protein the PGC-1α promoter and PGC-1α transcription PubMed Scopus PGC-1α the into the has been that in PGC-1α is in the PubMed Scopus However, as in in resting skeletal most of the PGC-1α is in the cytosol. protein as a of the of of the nuclear with proteins protein to the of exercise the of in of the nuclear the also in the of resting and as in the nuclear protein of resulted in a increase in the of PGC-1α in the and NRF-2 and transcription that in mitochondrial biogenesis PubMed Scopus the that activation rather than increased expression of PGC-1α mediates the initial phase of exercise-induced mitochondrial biogenesis, we and NRF-2 the to binding of to the binding the cytochrome c promoter and binding of NRF-2 to an NRF-2 binding the cytochrome oxidase subunit in and NRF-2 binding increased in response to a of before an increase in PGC-1α protein transcription coactivator PGC-1α regulates the expression of the mitochondrial proteins that mediate and Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PGC-1α mediates this and transcription that expression of mitochondrial proteins PubMed Scopus PubMed Scopus PubMed Scopus of PGC-1α in muscle cells results in increases in mitochondria, with of the and PubMed Scopus PubMed Scopus overexpression of PGC-1α increases the mitochondrial of skeletal muscle and of muscle to muscle PubMed Scopus an in skeletal muscle that is to that PGC-1α with increases in the of the mitochondrial of the citrate J.O. PubMed Scopus mitochondrial respiratory J.O. Physiol. PubMed Scopus J.O. PubMed and the J.O. Physiol. PubMed Scopus J.O. PubMed Scopus and increases in the to and J.O. PubMed J.O. PubMed Scopus J.O. Physiol. PubMed Scopus and J.O. PubMed in mitochondrial biogenesis is the of the transcription that the mitochondrial and most the of Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus has it to the exercise mitochondrial of that results in rapid increases in PGC-1α PubMed Scopus PubMed Scopus Physiol. Scopus and PGC-1 protein J.O. PubMed Scopus Physiol. PubMed Scopus in skeletal muscle. In of the finding that PGC-1α overexpression in cells PubMed Scopus PubMed Scopus and in of PubMed Scopus increases mitochondrial biogenesis, it that the exercise-induced of mitochondrial biogenesis is the increase in PGC-1α protein PubMed Scopus PubMed Scopus J.O. PubMed Scopus Physiol. PubMed Scopus PubMed Scopus However, an of the of the adaptive we of the mitochondrial proteins with short that PGC-1α to increase in with PGC-1α finding led to the that the initial phase of the adaptive increase in mitochondrial biogenesis exercise is activation of PGC-1α rather than the increase in PGC-1α protein results of the support this of is that the binding of the transcription factor to response the cytochrome c promoter and of NRF-2 to response the promoter increased in response to exercise prior to an increase in PGC-1α protein. and NRF-2 binding PGC-1α PubMed Scopus PubMed Scopus of that PGC-1α activation, rather than the increase in PGC-1α mediates the initial of mitochondrial biogenesis exercise is that the and protein of a of mitochondrial increased prior to the increase in PGC-1α our this is the that mitochondrial biogenesis increased activation of that PGC-1α regulates mitochondrial biogenesis has in PGC-1α of cells or increased overexpression or or in response to that increase mitochondrial biogenesis as or exercise Rev. PubMed Scopus PubMed Scopus However, it has also been that the of PGC-1α p38 MAPK Rev. PubMed Scopus PubMed Scopus PubMed Scopus This is of an binding protein PubMed Scopus it has been to of PGC-1α in skeletal muscle in it that this is in the of results in activation of p38 MAPK Physiol. PubMed Scopus PubMed Scopus Physiol. Scopus PubMed Scopus of p38 MAPK increased and PGC-1α promoter in PubMed Scopus Furthermore, overexpression of the p38 in resulted in increased expression of PGC-1α PubMed Scopus PubMed Scopus that activation of p38 is to the adaptive increase in mitochondrial biogenesis of to and the protein the PGC-1α promoter and increased PGC-1α expression PubMed Scopus PubMed Scopus that exercise results in activation of p38 and of with and support this However, we hypothesize that the increase in PGC-1α protein expression the phase of this adaptive response and that the initial phase increased of mitochondrial proteins activation of this study, we found that most of the PGC-1α in resting skeletal muscle is in the and that exercise movement of PGC-1α into the nucleus. This is in to cells in PGC-1α is to the PubMed Scopus our we the of Exercise results in activation of p38 and PGC-1α into the and the transcription and nuclear that expression of mitochondrial and mediates the phase of the adaptive of the PGC-1α promoter and transcription that as PubMed Scopus PubMed Scopus results in an increase in PGC-1α increase in PGC-1α protein mediates the phase of the and the increase in mitochondrial biogenesis activation of transcription coactivator PGC-1α regulates the expression of the mitochondrial proteins that mediate and Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus PGC-1α mediates this and transcription that expression of mitochondrial proteins PubMed Scopus PubMed Scopus PubMed Scopus of PGC-1α in muscle cells results in increases in mitochondria, with of the and PubMed Scopus PubMed Scopus overexpression of PGC-1α increases the mitochondrial of skeletal muscle and of muscle to muscle PubMed Scopus Exercise an in skeletal muscle that is to that PGC-1α with increases in the of the mitochondrial of the citrate J.O. PubMed Scopus mitochondrial respiratory J.O. Physiol. PubMed Scopus J.O. PubMed and the J.O. Physiol. PubMed Scopus J.O. PubMed Scopus and increases in the to and J.O. PubMed J.O. PubMed Scopus J.O. Physiol. PubMed Scopus and J.O. PubMed in mitochondrial biogenesis is the of the transcription that the mitochondrial and most the of Rev. PubMed Scopus PubMed Scopus PubMed Scopus PubMed Scopus has it to the exercise mitochondrial biogenesis. of that results in rapid increases in PGC-1α PubMed Scopus PubMed Scopus Physiol. Scopus and PGC-1 protein J.O. PubMed Scopus Physiol. PubMed Scopus in skeletal muscle. In of the finding that PGC-1α overexpression in cells PubMed Scopus PubMed Scopus and in of PubMed Scopus increases mitochondrial biogenesis, it that the exercise-induced of mitochondrial biogenesis is the increase in PGC-1α protein PubMed Scopus PubMed Scopus J.O. PubMed Scopus Physiol. PubMed Scopus PubMed Scopus However, an of the of the adaptive we of the mitochondrial proteins with short that PGC-1α to increase in with PGC-1α protein. This finding led to the that the initial phase of the adaptive increase in mitochondrial biogenesis exercise is activation of PGC-1α rather than the increase in PGC-1α protein results of the support this of is that the binding of the transcription factor to response the cytochrome c promoter and of NRF-2 to response the promoter increased in response to exercise prior to an increase in PGC-1α protein. and NRF-2 binding PGC-1α PubMed Scopus PubMed Scopus of that PGC-1α activation, rather than the increase in PGC-1α mediates the initial of mitochondrial biogenesis exercise is that the and protein of a of mitochondrial increased prior to the increase in PGC-1α protein. our this is the that mitochondrial biogenesis increased activation of that PGC-1α regulates mitochondrial biogenesis has in PGC-1α of cells or increased overexpression or or in response to that increase mitochondrial biogenesis as or exercise Rev. PubMed Scopus PubMed Scopus However, it has also been that the of PGC-1α p38 MAPK Rev. PubMed Scopus PubMed Scopus PubMed Scopus This is of an binding protein PubMed Scopus it has been to of PGC-1α in skeletal muscle in it that this is in the of results in activation of p38 MAPK Physiol. PubMed Scopus PubMed Scopus Physiol. Scopus PubMed Scopus of p38 MAPK increased and PGC-1α promoter in PubMed Scopus Furthermore, overexpression of the p38 in resulted in increased expression of PGC-1α PubMed Scopus PubMed Scopus that activation of p38 is to the adaptive increase in mitochondrial biogenesis of to and the protein the PGC-1α promoter and increased PGC-1α expression PubMed Scopus PubMed Scopus that exercise results in activation of p38 and of with and support this However, we hypothesize that the increase in PGC-1α protein expression the phase of this adaptive response and that the initial phase increased of mitochondrial proteins activation of In this study, we found that most of the PGC-1α in resting skeletal muscle is in the and that exercise movement of PGC-1α into the nucleus. This is in to cells in PGC-1α is to the PubMed Scopus our we the of Exercise results in activation of p38 and PGC-1α into the and the transcription and nuclear that expression of mitochondrial and mediates the phase of the adaptive of the PGC-1α promoter and transcription that as PubMed Scopus PubMed Scopus results in an increase in PGC-1α increase in PGC-1α protein mediates the phase of the and the increase in mitochondrial biogenesis activation of to with of the
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