Bioenergetic Analysis of Peroxisome Proliferator-activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle Cells
Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metabolism, particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1α has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary analysis has suggested that this molecule may specifically increase the fraction of uncoupled versus coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1α and its homolog PGC-1β in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1α or PGC-1β display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1α have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1β. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1β preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1α and PGC-1β profoundly alter mitochondrial metabolism and suggest that these proteins are likely to play different physiological functions. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metabolism, particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1α has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary analysis has suggested that this molecule may specifically increase the fraction of uncoupled versus coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1α and its homolog PGC-1β in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1α or PGC-1β display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1α have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1β. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1β preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1α and PGC-1β profoundly alter mitochondrial metabolism and suggest that these proteins are likely to play different physiological functions. Mitochondria play a central role in metabolism by coupling cellular respiration to the production of ATP. However, this coupling is not perfectly tight. Indeed, it is estimated that approximately 20% of the standard metabolic rate in mammals is due to a leak of protons across the mitochondrial inner membrane in a manner that uncouples cellular respiration from ATP production, thereby generating heat (1Rolfe D.F. Brown G.C. Physiol. Rev. 1997; 77: 731-758Crossref PubMed Scopus (1404) Google Scholar). This cycle is called basal proton leak. In addition to this basal leak, there is an inducible leak of protons catalyzed by uncoupling protein 1 (UCP1) 1The abbreviations used are: UCP, uncoupling protein; ROS, reactive oxygen species; PGC, peroxisome proliferator-activated receptor γ coactivator; GFP, green fluorescent protein; TPMP, [3H]triphenylmethylphosphonium; PPAR, peroxisome proliferator-activated receptor. in brown fat. Two close homologs of this protein have been discovered, UCP2 and UCP3 (2Fleury C. Neverova M. Collins S. Raimbault S. Champigny O. Levi-Meyrueis C. Bouillaud F. Seldin M.F. Surwit R.S. Ricquier D. Warden C.H. Nat. Genet. 1997; 15: 269-272Crossref PubMed Scopus (1562) Google Scholar, 3Gimeno R.E. Dembski M. Weng X. Deng N. Shyjan A.W. Gimeno C.J. Iris F. Ellis S.J. Woolf E.A. Tartaglia L.A. Diabetes. 1997; 46: 900-906Crossref PubMed Scopus (0) Google Scholar, 4Boss O. Samec S. Paoloni-Giacobino A. Rossier C. Dulloo A. Seydoux J. Muzzin P. Giacobino J.P. 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Brand M.D. Nature. 2002; 415: 96-99Crossref PubMed Scopus (1155) Google Scholar) and the modulation of cellular ATP levels, especially in insulin-secreting β cells (9Zhang C.Y. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig A.J. Boss O. Kim Y.B. Zheng X.X. Wheeler M.B. Shulman G.I. Chan C.B. Lowell B.B. Cell. 2001; 105: 745-755Abstract Full Text Full Text PDF PubMed Scopus (828) Google Scholar, 10Krauss S. Zhang C.Y. Lowell B.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 118-122Crossref PubMed Scopus (154) Google Scholar). Interestingly, none of the genetic studies using either knockout mice or mice overexpressing moderate levels of UCP2 and UCP3 show a significant effect of these proteins in determining standard metabolic rate by uncoupling cellular respiration (11Argyropoulos G. Harper M.E. J. Appl. Physiol. 2002; 92: 2187-2198Crossref PubMed Scopus (218) Google Scholar, 12Nedergaard J. Cannon B. Exp. Physiol. 2003; 88: 65-84Crossref PubMed Scopus (191) Google Scholar). Many changes in the cellular environment result in modulation of mitochondrial metabolism. Basal proton leak rate changes in response to hormonal status and metabolic depression (13Hafner R.P. Nobes C.D. McGown A.D. Brand M.D. Eur. J. Biochem. 1988; 178: 511-518Crossref PubMed Scopus (132) Google Scholar, 14Hafner R.P. Leake M.J. Brand M.D. FEBS Lett. 1989; 248: 175-178Crossref PubMed Scopus (40) Google Scholar, 15Nobes C.D. Brown G.C. Olive P.N. Brand M.D. J. Biol. Chem. 1990; 265: 12903-12909Abstract Full Text PDF PubMed Google Scholar, 16Harper M.E. Ballantyne J.S. Leach M. Brand M.D. Biochem. Soc. Trans. 1993; 21: 785-792Crossref PubMed Scopus (55) Google Scholar, 17Harper M.E. Brand M.D. J. Biol. Chem. 1993; 268: 14850-14860Abstract Full Text PDF PubMed Google Scholar, 18St-Pierre J. Brand M.D. Boutilier R.G. J. Exp. Biol. 2000; 203: 1469-1476Crossref PubMed Google Scholar, 19Bishop T. St-Pierre J. Brand M.D. Am. J. Physiol. 2002; 282: R372-R382PubMed Google Scholar). Also, small mammals with high standard metabolic rates have higher proton leak rates than large mammals with low standard metabolic rates (20Porter R.K. Brand M.D. Nature. 1993; 362: 628-630Crossref PubMed Scopus (214) Google Scholar, 21Porter R.K. Brand M.D. Am. J. Physiol. 1995; 269: R1213-R1224PubMed Google Scholar). Furthermore, proton leak rates differ between phylogenetic groups; it is higher in endotherms than in ectotherms (22Brand M.D. Couture P. Else P.L. Withers K.W. Hulbert A.J. Biochem. J. 1991; 275: 81-86Crossref PubMed Scopus (226) Google Scholar). The fact that mitochondrial functions can be altered in response to environmental stimuli is due to the execution of a coordinated program of genes expression. PPARγ coactivator-1α (PGC-1α) has been shown to be a powerful regulator of multiple aspects of mitochondrial gene expression. Indeed, PGC-1α is cold-induced in brown fat and muscle where it plays a role in adaptive thermogenesis by regulating a complex program of increased mitochondrial biogenesis and uncoupled respiration via coactivation of peroxisome proliferator-activated receptors (PPARs), nuclear respiratory factor 1, and perhaps other transcription factors (23Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (3102) Google Scholar, 24Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar). Furthermore, transgenic mice expressing physiological levels of PGC-1α protein in skeletal muscle display an increased content of oxidative type I fibers compared with their wild-type counterparts (25Lin J. Wu H. Tarr P.T. Zhang C.Y. Wu Z. Boss O. Michael L.F. Puigserver P. Isotani E. Olson E.N. Lowell B.B. Bassel-Duby R. Spiegelman B.M. Nature. 2002; 418: 797-801Crossref PubMed Scopus (2072) Google Scholar). Homologs of PGC-1α have been discovered, namely PGC-1β (26Lin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. J. Biol. Chem. 2002; 277: 1645-1648Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 27Kressler D. Schreiber S.N. Knutti D. Kralli A. J. Biol. Chem. 2002; 277: 13918-13925Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar) and PGC-1-related coactivator (28Andersson U. Scarpulla R.C. Mol. Cell. Biol. 2001; 21: 3738-3749Crossref PubMed Scopus (300) Google Scholar). The expression of PGC-1β and PGC-1-related coactivator is not cold-inducible in brown fat and skeletal muscle, suggesting that they might have distinct roles from PGC-1α (26Lin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. J. Biol. Chem. 2002; 277: 1645-1648Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 28Andersson U. Scarpulla R.C. Mol. Cell. Biol. 2001; 21: 3738-3749Crossref PubMed Scopus (300) Google Scholar). However, both PGC-1β and PGC-1-related coactivator coactivate nuclear respiratory factor 1, implying that they may also have a role in mitochondrial metabolism (26Lin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. J. Biol. Chem. 2002; 277: 1645-1648Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 28Andersson U. Scarpulla R.C. Mol. Cell. Biol. 2001; 21: 3738-3749Crossref PubMed Scopus (300) Google Scholar). To date, there are no bioenergetic mechanisms that might explain how PGC-1α increases uncoupled respiration, nor any studies examining a role for its closest homolog PGC-1β in mitochondrial metabolism. In this report, we measure the respiration and proton leak kinetics of muscle cells expressing either PGC-1α or PGC-1β. that increases mitochondrial metabolism. Although both PGC-1α and PGC-1β increase proton leak, cells expressing PGC-1α have a higher proportion of their mitochondrial respiration linked to proton leak than expressing PGC-1β. in with at The of by the standard of the cells to and the to with The The cells with expressing GFP, or PGC-1β. The and PGC-1α using the expression a the PGC-1β by of the the and of the with cells using T. C.B. Biol. PubMed Scopus Google Scholar). Two of the cells to mitochondrial membrane respiration mitochondrial and The cells by with and for with to the and the cells and at for at the cells in with 1 and using In approximately or in leak kinetics analyses in cells as in M. Brown G. C. The cells for with TPMP, and as as as of cells. to that the for of cells. this the respiration rates and membrane The of proton leak the respiration rate and membrane potential of cells in the of of and to membrane potential and respiration and to respiration. respiration from the respiration to mitochondrial respiration. To membrane we used the mitochondrial in the of cells not shown using the in M. Brown G. C. membrane potential of J. A. J. PubMed Scopus Google and the and M.E. Brand M.D. J. Biol. Chem. 1993; 268: 14850-14860Abstract Full Text PDF PubMed Google Scholar, M. Brown G. C. Scholar). of ATP and to of ATP and proton leak to mitochondrial respiration from the of the proton leak ATP the fraction of mitochondrial respiration to leak the fraction of mitochondrial respiration that is to for 1 in a of and in in with for 1 in and in for by in of at at and at The and in a to with and and in a The of mitochondrial and of cells expressing GFP, and PGC-1β as in E. for of Mitochondria from and transgenic mice expressing PGC-1α from the muscle in the muscle a cycle and (25Lin J. Wu H. Tarr P.T. Zhang C.Y. Wu Z. Boss O. Michael L.F. Puigserver P. Isotani E. Olson E.N. Lowell B.B. Bassel-Duby R. Spiegelman B.M. Nature. 2002; 418: 797-801Crossref PubMed Scopus (2072) Google Scholar). The mice and their muscle and with The in at and in a with using a The at at for The and at for The and the in and at for The and the in of The protein of the mitochondrial using the with as a in proton leak kinetics in as in M. Brown G. C. Mitochondria in and 1 at in a at using a The oxygen consumption with a and the membrane potential using a mitochondrial and at the of to for Mitochondria and the to to mitochondrial respiration and membrane potential. to the of the The oxygen of the of B. Biochem. PubMed Scopus Google and the mitochondrial M. Brown G. C. Scholar). from using of by and a The with of the analyses performed using of the of ATP and proton leak to mitochondrial respiration between cells with and PGC-1α or with and PGC-1β with of mitochondrial and between and cells with analysis of and the a of Cells PGC-1α or the functions of PGC-1α and these expressed with in muscle cells. cells used skeletal muscle in both the cells of these an for shown these levels of PGC-1α and PGC-1β In for several genes of PGC-1α and are in cells with PGC-1α or PGC-1β. the proton in these cells, as as cells expressing a control can be as the of protons across the mitochondrial membrane at a given membrane potential and the fraction of mitochondrial respiration that is not coupled to ATP the consumption of is used as a for proton leak M. Brown G. C. Scholar). The of a proton leak the respiration rate and membrane potential of in the of an of the M. Brown G. C. Scholar). respiration and membrane potential are by of a of the M. Brown G. C. Scholar). shown in 1 and the respiration rate of and cells at any given membrane potential higher than the respiration rate at of PGC-1α cells and the control and of cells, an increase of The respiration rate of PGC-1β cells and the control at and of cells, a increase To the proton leak kinetics of the cells expressing PGC-1α and we expressed the respiration rates and membrane of these cells as of the respiration rate and membrane potential of The proton of cells expressing PGC-1β approximately higher than expressing PGC-1α Indeed, the respiration rate of when to its at that of PGC-1α cells at any given membrane potential of ATP and to PGC-1-related respiration is two ATP and proton leak. ATP is the fraction of mitochondrial respiration coupled to ATP production and is to leak is the fraction of mitochondrial respiration not coupled to ATP production and is to the between the ATP and proton leak when mitochondrial respiration is metabolic can be ATP and proton leak are in a similar mitochondrial respiration metabolic be both ATP and proton leak the proportion of mitochondrial respiration to ATP and proton leak in cells expressing and used two different to this has its they a of the metabolic of these cells. In the we expressed the respiration rate of and cells in the of as a fraction of their mitochondrial respiration not membrane potential The potential with this is that it not membrane potential of the different cells. this cells of their mitochondrial respiration to proton leak, compared with for In other PGC-1α increases uncoupled respiration than coupled respiration. This is in with the by Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar) using with that PGC-1α increases uncoupled respiration than coupled respiration. In cells expressing PGC-1β display a fraction of mitochondrial respiration by proton leak similar to that of the Indeed, the ATP and proton leak increased in cells that they are as coupled as control cells a we the membrane potential and the proportion of mitochondrial respiration to proton leak at the membrane potential of and cells. This is the membrane potential in the of not The membrane potential of these cells higher in the than in the of is the of the proton leak in To the proton leak rate at the membrane potential of these cells, we a the proton leak of PGC-1β cells, and from 1 and T. St-Pierre J. Brand M.D. Am. J. Physiol. 2002; 282: R372-R382PubMed Google Scholar). with this is that the proton leak rate at the membrane potential of these cells be to measure it this we that cells expressing GFP, and PGC-1β have and of their mitochondrial respiration linked to proton leak. Although these are higher than the in the the cells expressing PGC-1α are than or cells. PGC-1β the fraction of respiration to proton leak detailed of Cells PGC-1α or in mitochondrial and changes in the of as membrane and are factors proton in cells R.K. Brand M.D. Am. J. Physiol. 1995; 269: R1213-R1224PubMed Google Scholar). To the increased proton of cells expressing PGC-1α or PGC-1β with mitochondrial we analyses of these cells and of via To mitochondrial a and the of expressed as a fraction of the E. for Scholar). used to the of E. for Scholar). cells expressing PGC-1α and PGC-1β and increases in mitochondrial compared with and the of we that from expressing PGC-1α a increase in compared with significant and from expressing GFP, and PGC-1β. of the increase in mitochondrial in cells expressing PGC-1α and PGC-1β compared with cells. from the increased in cells compared with The indicate mitochondrial of Mitochondria from PGC-1α cells expressing PGC-1α and PGC-1β increased proton leak we to this effect in However, this type of has been with cells of the with large we of the of mice expressing PGC-1α in skeletal muscle and compared the proton leak kinetics of from their muscle with that of wild-type these mice not this coactivator; they PGC-1α in type muscle fibers at the in type I fibers (25Lin J. Wu H. Tarr P.T. Zhang C.Y. Wu Z. Boss O. Michael L.F. Puigserver P. Isotani E. Olson E.N. Lowell B.B. Bassel-Duby R. Spiegelman B.M. Nature. 2002; 418: 797-801Crossref PubMed Scopus (2072) Google Scholar). the of mitochondrial proteins from a given muscle higher in transgenic mice than in wild-type not suggesting that the expression of PGC-1α in also to mitochondrial The of a proton leak in the respiration rate and membrane potential. shown in from transgenic mice a higher respiration rate than from wild-type mice at any given membrane potential. In the respiration rate higher in from transgenic than wild-type suggesting an increased Together, these are with the performed in cells and that PGC-1α can the of proton leak in Cells PGC-1α or the for the changes in respiration and proton leak, we the expression of several mitochondrial components of the and the metabolism of and as as uncoupling proteins and The expression of involved in the metabolism of and also the increased mitochondrial and respiration of PGC-1α and PGC-1β cells to cellular levels of shown in cells with these expressed similar levels of PGC-1α or PGC-1β and both for the PGC-1α genes and UCP2 to the the expression of ATP UCP2 and UCP3 as as and higher in cells expressing PGC-1α and PGC-1β than in control cells The in the expression of for certain ATP and in PGC-1α and cells the and in their mitochondrial and and higher of at The fact that expression of these a higher than the mitochondrial suggests that might have an content of these proteins. Together, these the that expressing PGC-1α and PGC-1β have an increased mitochondrial and also suggest that these cells have with different Interestingly, PGC-1β cells a higher expression of two involved in the metabolism of ROS, and compared with PGC-1α and cells The coactivator PGC-1α has been shown to induce mitochondrial biogenesis in as as skeletal and (23Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (3102) Google Scholar, 24Wu Z. Puigserver P. Andersson U. Zhang C. Adelmant G. Mootha V. Troy A. Cinti S. Lowell B. Scarpulla R.C. Spiegelman B.M. Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar, A. J. 2000; PubMed Scopus Google Scholar). studies using the suggested that PGC-1α might specifically induce an increased proton leak in skeletal muscle cells, these studies to be a of in proton leak can be by examining and control cells at different mitochondrial membrane In this we have performed a and analysis of the of PGC-1α and the coactivator PGC-1β the of is PGC-1β has the to induce mitochondrial biogenesis and increase respiration. shown in and PGC-1β mitochondrial biogenesis and respiration. Indeed, it is in this than PGC-1α at similar levels of several genes are by both to a similar in this is the fraction of mitochondrial respiration coupled or uncoupled in cells expressing PGC-1α or PGC-1β. are several for the increased fraction of uncoupled respiration in the of PGC-1α versus PGC-1β. it is to how coupled and uncoupled respiration in can be factor that with to respiration rate to the mitochondrial of these cells. can for the in mitochondrial between cells expressing PGC-1α or PGC-1β and control cells by the respiration rates of these cells by their mitochondrial This an of the respiration rate of the cells. for in mitochondrial the respiration rate of cells expressing PGC-1α or PGC-1β is similar to control cells. However, the proton leak rate of the proton leak in of cells expressing PGC-1α higher than that of cells expressing PGC-1β or control cells, both of have similar proton leak rates data suggest the proton leak rate of is higher in the of PGC-1α than PGC-1β and that mitochondrial is not the for the higher fraction of respiration in cells expressing in the of explain higher proton leak rates in cells expressing PGC-1α versus PGC-1β. Cells expressing not a significant increase of in and be to their proton leak by the of membrane across protons can the In of the that PGC-1α levels increase the proton leak of a using from the skeletal muscle of mice expressing PGC-1α at the in type I muscle fibers that these have higher proton leak rate of proton the leak in and proton than from wild-type in the of play an important role in the between PGC-1α and PGC-1β for the proportion of mitochondrial respiration linked to proton leak. between cells expressing PGC-1α and PGC-1β to the function of the uncoupling that is the expression of UCP2 with altered levels of activators of the Cells expressing PGC-1α and PGC-1β both expression levels of UCP2 and UCP3 cells expressing PGC-1β increased levels of two genes, namely and both involved in the of is or that both PGC-1α and PGC-1β result in the of via the of mitochondrial metabolism, thereby UCP2 However, it is also that PGC-1β is at the removal of these for two a role in metabolism of are by this coactivator not by of in the can the of the inner mitochondrial membrane and UCP2 or UCP3 is an K.S. Brand M.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The of PGC-1α and PGC-1β to and via this to be important to in this analysis ATP the fraction of mitochondrial respiration ATP for the ATP are important ATP between cells expressing PGC-1α and PGC-1β. Indeed, of the increase in mitochondrial respiration in cells expressing PGC-1β due to an increase in ATP and by an increase in proton leak. cells expressing the of the increase in mitochondrial respiration in these cells due to an increase in ATP and by an increase in proton leak. Together, these data indicate that the of the ATP increased in cells expressing potential to the higher fraction of coupled respiration in these cells. the data indicate that the of the respiration by PGC-1α or PGC-1β is Indeed, cells expressing PGC-1α have a mitochondrial respiration than expressing PGC-1β or This is particularly in of the fact that PGC-1α is in the in both brown fat and skeletal muscle, two (23Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Abstract Full Text Full Text PDF PubMed Scopus (3102) Google Scholar). In not to a particularly mitochondrial metabolism is not cold-inducible in these (26Lin J. Puigserver P. Donovan J. Tarr P. Spiegelman B.M. J. Biol. Chem. 2002; 277: 1645-1648Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). However, it is important to that PGC-1α is also in muscle by and is expressed in type 1 muscle, muscle with to Also, PGC-1α can induce an increase in type 1 fibers in muscle of type fibers (25Lin J. Wu H. Tarr P.T. Zhang C.Y. Wu Z. Boss O. Michael L.F. Puigserver P. Isotani E. Olson E.N. Lowell B.B. Bassel-Duby R. Spiegelman B.M. Nature. 2002; 418: 797-801Crossref PubMed Scopus (2072) Google Scholar). Furthermore, PGC-1α is expressed in the a ATP mitochondrial uncoupling in these be to cause a in skeletal muscle and can be by an of the of ATP and proton leak mitochondrial membrane potential In a of as in muscle or cold-induced muscle or brown a low ATP cause an increased mitochondrial membrane in increase proton leak. In high ATP the of membrane in a coupling of metabolism proton leak as membrane potential is by a uncoupled at a where ATP as the of proton leak. in proton leak at it ATP when this is metabolic both PGC-1α and PGC-1β are in many the expression levels of these likely play an important role in metabolic for for the and B. Lowell for a of the