Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity
Open accessAbstract
Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α(-/-)β(f/f/MLC-Cre) mice) were generated and characterized. PGC-1α(-/-)β(f/f/MLC-Cre) mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α(-/-)β(f/f/MLC-Cre) mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.
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Insulin-stimulated glucose sensitivity is increased in some mouse models of mitochondrial dysfunction.
“Along the same line, insulin-stimulated glucose sensitivity is increased in some mouse models of mitochondrial dysfunction (Wredenberg et al, 2006; Pospisilik et al, 2007; Zechner et al, 2010).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Zechner et al, 2010
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Baar, K., Wende, A. R., Jones, T. E., Marison, M., Nolte, L. A., Chen, M., Kelly, D. P., & Holloszy, J. O. (2002) · The FASEB Journal · doi:10.1096/fj.02-0367com · Cited by 1,020 · cited 2× · see citing works
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Waterham, H. R., Koster, J., van Roermund, C. W. T., Mooyer, P. A. W., Wanders, R. J. A., & Leonard, J. V. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa064436 · Cited by 749 · cited 2× · see citing works
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“Significant evidence suggests a link between skeletal muscle mitochondrial dysfunction and the development of insulin resis- tance (Lowell and Shulman, 2005; Morino et al., 2005; Petersen et al., 2005).”
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“…mouse ‘‘knockout’’ studies to date have been limited due to the functionally redundant actions of PGC-1a and PGC-1b; single PGC-1 gene deletion lines exhibit relatively minimal phenotypes (Lin et al., 2004; Leone et al., 2005; Lelliott et al., 2006; Vianna et al., 2006; Sonoda et al., 2007).”
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ResultSelf-citationcDNA Cloning and mRNA Analysis of PGC-1 in Epitrochlearis Muscle in Swimming-Exercised Rats
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Wende, A. R., Schaeffer, P. J., Parker, G. J., Zechner, C., Han, D.-H., Chen, M. M., Hancock, C. R., Lehman, J. J., Huss, J. M., McClain, D. A., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707006200 · Cited by 257 · cited 2× · see citing works
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“PGC-1 overexpression in mice has been shown to inhibit the protein degrada- tion known to occur in disuse atrophy (Wenz et al., 2009; Brault et al., 2010).”
BackgroundVoluntary running induces fiber type-specific angiogenesis in mouse skeletal muscle
Waters, R. E., Rotevatn, S., Li, P., Annex, B. H., & Yan, Z. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00247.2004 · Cited by 214 · cited 1× · see citing works
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“Consistent with the type II fiber specificity of the MLC-1f promoter (Donoghue et al., 1991; Parsons et al., 2004), PGC-1b gene expression was markedly reduced in gastrocnemius (GC) (residual levels 10.9% ± 1.3% of PGC-1bf/f) and white vastus (9.0% ± 1.5% of PGC-1bf/f) muscles of PGC-1bf/f/MLC-Cre…”
BackgroundInfluentialHypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance.
Vianna, C. R., Huntgeburth, M., Coppari, R., Choi, C. S., Lin, J., Krauss, S., Barbatelli, G., Tzameli, I., Kim, Y.-B., Cinti, S., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.11.003 · Cited by 181 · cited 4× · see citing works
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BackgroundInfluentialMitochondrial Fusion Is Increased by the Nuclear Coactivator PGC-1β
Liesa, M., Borda-d'Agua, B., Medina‐Gómez, G., Lelliott, C. J., Paz, J. C., Rojo, M., Palacı́n, M., Vidal‐Puig, A., & Zorzano, A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003613 · Cited by 175 · cited 2× · see citing works
“Others have recently shown that PGC-1a and PGC-1b are capable of activating transcription of the Mfn2 gene by coactivating the nuclear receptor ERRa (Soriano et al., 2006; Liesa et al., 2008).”
BackgroundCaMKII?-cre transgene expression and recombination patterns in the mouse brain
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Alternative mRNA Splicing Produces a Novel Biologically Active Short Isoform of PGC-1α
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“One caveat to our conclusions is that a small amount of a mutant form of a naturally occurring, alterna- tively spliced form of PGC-1a, referred to as NT-PGC-1a (Zhang et al., 2009), could be theoretically expressed in the PGC-1a-defi- cient line used in this study.”
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“This latter function has been ascribed to the ongoing dynamics of fusion and fission, which serve to maintain mitochondrial quality control (Chen et al., 2005; Waterham et al., 2007; Zhang and Chan, 2007).”
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“Consistent with the type II fiber specificity of the MLC-1f promoter (Donoghue et al., 1991; Parsons et al., 2004), PGC-1b gene expression was markedly reduced in gastrocnemius (GC) (residual levels 10.9% ± 1.3% of PGC-1bf/f) and white vastus (9.0% ± 1.5% of PGC-1bf/f) muscles of PGC-1bf/f/MLC-Cre…”
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“Mice were euthanized by CO2 inhalation after 10 weeks on high-fat diet, and plasma and tissue triglyceride concentrations were determined by colorimetric assays as previously described (Chen et al., 2008).”
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BackgroundMethodSelf-citation
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“Accordingly, exercise performance, in this model, is greatly decreased compared to single PGC-1α or PGC-1β knockout animals (Zechner et al., 2010).”
BackgroundInfluentialPGC-1α-mediated regulation of mitochondrial function and physiological implications
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“Zechner C, et al. (2010) Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity.”
BackgroundInfluentialInsulin Resistance and Type 2 Diabetes
Taylor, R. (2012) · Diabetes · doi:10.2337/db12-0073 · Cited by 394 · see citing works
“Exercise can reduce insulin resistance and ameliorate mitochondrial dysfunction (17), whereas established mitochondrial dysfunction does not necessarily produce insulin resistance in animal models or in humans (18,19).”
BackgroundAMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
O’Neill, H. M., Holloway, G. P., & Steinberg, G. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.019 · Cited by 364 · see citing works
“Mitochondrial oxidative capacity is important for endurance exercise performance, and has been highlighted by recent findings in muscle specific PGC-1a/b null mice (Zechner et al., 2010).”
BackgroundLu, Q., Zhu, Y., Deng, C., Liang, Z., Chen, J., Chen, Y., Wang, X., Liu, Y., Tian, Y., & Yang, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01756-w · Cited by 360 · see citing works
Yan, Z., Okutsu, M., Akhtar, Y., & Lira, V. A. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00993.2010 · Cited by 338 · see citing works
Self-citationMolecular Mechanisms Underlying Cardiac Adaptation to Exercise
Vega, R. B., Konhilas, J. P., Kelly, D. P., & Leinwand, L. A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.025 · Cited by 312 · see citing works
Self-citationMuscle fiber type diversification during exercise and regeneration
Qaisar, R., Bhaskaran, S., & Van Remmen, H. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.03.025 · Cited by 283 · see citing works
“PGC-1α and PPARβ also participate in regulating slow oxidative phenotype [227] in response to EE, although PGC-1α is probably more involved in maintaining rather than inducing a slow-twitch phenotype [228].”
BackgroundSkeletal muscle mitochondrial remodeling in exercise and diseases
Gan, Z., Fu, T., Kelly, D. P., & Vega, R. B. (2018) · Cell Research · doi:10.1038/s41422-018-0078-7 · Cited by 287 · see citing works
Self-citationMolecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle
Drake, J. C., Wilson, R. J., & Yan, Z. (2016) · The FASEB Journal · doi:10.1096/fj.15-276337 · Cited by 263 · see citing works
“Furthermore, muscle-specific deletion of Pgc-1a showed compromised exercise performance, along with a reduction in several markers for mitochondrial biogenesis (16, 17), as well as blunted mitochondrial biogenesis after exercise training (18).”
BackgroundSelf-citationEgan, B., & Sharples, A. P. (2023) · Physiological Reviews · doi:10.1152/physrev.00054.2021 · Cited by 278 · see citing works
Flockhart, M., Nilsson, L. C., Tais, S., Ekblom, B. T., Apró, W., & Larsen, F. J. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.017 · Cited by 264 · see citing works
CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice
Zhang, Y., Long, C., Li, H. Z., McAnally, J., Baskin, K. K., Shelton, J. M., Bassel‐Duby, R., & Olson, E. N. (2017) · Science Advances · doi:10.1126/sciadv.1602814 · Cited by 228 · see citing works
Skeletal muscle mitochondria: A major player in exercise, health and disease
Russell, A. P., Foletta, V. C., Snow, R. J., & Wadley, G. D. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.11.016 · Cited by 223 · see citing works
Russell, A. P., Wada, S., Vergani, L., Hock, M. B., Lamon, S., Léger, B., Ushida, T., Cartoni, R., Wadley, G. D., Hespel, P., et al. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.08.015 · Cited by 224 · see citing works
Hyatt, H. W., Deminice, R., Yoshihara, T., & Powers, S. K. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.11.005 · Cited by 219 · see citing works
“It follows that decreases in PGC-1α abundance results in impaired mitochondrial biogenesis resulting in a negative impact on mitochondrial structure and function [66].”
BackgroundMartin, O. J., Lai, L., Soundarapandian, M. M., Leone, T. C., Zorzano, A., Keller, M. P., Attie, A., Muoio, D. M., & Kelly, D. P. (2013) · Circulation Research · doi:10.1161/circresaha.114.302562 · Cited by 213 · see citing works
“The importance of mitochondrial respiration for proper heart function is demonstrated by the tight linear relationship between cardiac oxygen consumption and work.(1) Evidence is emerging that in many forms of heart failure, cardiac mitochondria revert to prenatal levels of function and morphology, leading to energy s…”
BackgroundSelf-citationNuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism
Gan, Z., Rumsey, J. W., Hazen, B. C., Lai, L., Leone, T. C., Vega, R. B., Xie, H., Conley, K. E., Auwerx, J. H., Smith, S. R., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67652 · Cited by 198 · see citing works
Self-citationExercise and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERRγ
Narkar, V. A., Fan, W., Downes, M., Yu, R. T., Jonker, J. W., Alaynick, W. A., Banayo, E., Karunasiri, M. S., Lorca, S., & Evans, R. M. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.019 · Cited by 185 · see citing works
Exercise Mimetics: Impact on Health and Performance
Fan, W., & Evans, R. M. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.10.022 · Cited by 188 · see citing works
Chen, L., Qin, Y. H., Liu, B., Gao, M. Q., Li, A., Li, X., & Gong, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.871357 · Cited by 172 · see citing works
Iqbal, S., Ostojic, O., Singh, K., Joseph, A., & Hood, D. A. (2013) · Muscle & Nerve · doi:10.1002/mus.23838 · Cited by 169 · see citing works
“Mice deficient in PGC-1a have reduced expression of Mfn2 mRNA.(36) Conversely, up-regulation in PGC-1a, from a single bout of cycling exercise stimulated ERRa binding at the 2413/”
BackgroundThe ageing neuromuscular system and sarcopenia: A mitochondrial perspective
Rygiel, K. A., Picard, M., & Turnbull, D. M. (2016) · The Journal of Physiology · doi:10.1113/jp271212 · Cited by 165 · see citing works
“…a close homologue of PGC-1α, has been shown to stimulate mitochondrial biogenesis in an equally robust manner, and deletion of both PGC-1α and PGC-1β from muscle down-regulates mitochondrial function much more dramatically than deletion of either alone (Arany et al. 2007; Zechner et al. 2010).”
BackgroundSirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis
Menzies, K. J., Singh, K., Saleem, A., & Hood, D. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.431155 · Cited by 167 · see citing works
Unravelling the mechanisms regulating muscle mitochondrial biogenesis
Hood, D. A., Tryon, L. D., Carter, H. N., Kim, Y., & Chen, C. C. W. (2016) · Biochemical Journal · doi:10.1042/bcj20160009 · Cited by 159 · see citing works
Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle
Kim, Y., Triolo, M., & Hood, D. A. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/3165396 · Cited by 158 · see citing works
Insulin Resistance and Mitochondrial Dysfunction
González-Franquesa, A., & Patti, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_25 · Cited by 154 · see citing works
Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy
Bentzinger, C. F., Lin, S., Romanino, K., Castets, P., Guridi, M., Summermatter, S., Handschin, C., Tintignac, L. A., Hall, M. N., & Rüegg, M. A. (2013) · Skeletal Muscle · doi:10.1186/2044-5040-3-6 · Cited by 153 · see citing works
“Moreover, depletion of both PGC1α and PGC1β results in much more severe loss of oxidative capacity than depletion of either protein alone [61].”
Quiat, D., Voelker, K. A., Pei, J., Grishin, N. V., Grange, R. W., Bassel‐Duby, R., & Olson, E. N. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1107413108 · Cited by 151 · see citing works
Beclin 2 Functions in Autophagy, Degradation of G Protein-Coupled Receptors, and Metabolism
He, C., Wei, Y., Sun, K., Li, B., Dong, X., Zou, Z., Liu, Y., Kinch, L. N., Khan, S., Sinha, S. C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.07.035 · Cited by 150 · see citing works
Maurya, S. K., Bal, N. C., Sopariwala, D. H., Pant, M., Rowland, L. A., Shaikh, S. A., & Periasamy, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.636878 · Cited by 146 · see citing works
“Next we studied whether the oxidative capacity was enhanced in muscle by determining SDH activity staining using succinate as substrate (22).”
MethodMitochondrial response to nutrient availability and its role in metabolic disease
Gao, A. W., Cantó, C., & Houtkooper, R. H. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303782 · Cited by 148 · see citing works
Jones, A. W. E., Yao, Z., Vicencio, J. M., Karkucińska‐Więckowska, A., & Szabadkai, G. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.09.009 · Cited by 145 · see citing works
“, named PGC-1β (Kressler et al., 2002; Lin et al., 2002a) and PGC-1α related coactivator (Andersson and Scarpulla, 2001) (PRC), as well as a truncated alternatively spliced isoform, NT-PGC-1α (Zechner et al., 2010; Zhang et al., 2009).”
BackgroundInfluentialThe nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2
Gan, Z., Burkart-Hartman, E. M., Han, D.-H., Finck, B., Leone, T. C., Smith, E. Y., Ayala, J. E., Holloszy, J., & Kelly, D. P. (2011) · Genes & Development · doi:10.1101/gad.178434.111 · Cited by 138 · see citing works
“Electron microscopy was performed as previously described (Zechner et al. 2010).”
MethodSelf-citationFiorenza, M., Gunnarsson, T. P., Hostrup, M., Iaia, F. M., Schena, F. F., Pilegaard, H., & Bangsbo, J. (2018) · The Journal of Physiology · doi:10.1113/jp275972 · Cited by 132 · see citing works
Sarcolipin: A Key Thermogenic and Metabolic Regulator in Skeletal Muscle
Pant, M., Bal, N. C., & Periasamy, M. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.08.006 · Cited by 133 · see citing works
“PGC1/, PGC1b Skeletal muscle specific double knockout Decreased exercise performance, decreased oxidative capacity, mitochondrial structural derangements [88]”
Kelly, D. P. (2012) · Science · doi:10.1126/science.1221688 · Cited by 132 · see citing works
Self-citationLeptin regulation of Hsp60 impacts hypothalamic insulin signaling
Kleinridders, A., Lauritzen, H. P. M. M., Ussar, S., Christensen, J. H., Mori, M. A., Bross, P., & Kahn, C. R. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67615 · Cited by 130 · see citing works
Coupling of mitochondrial function and skeletal muscle fiber type by a miR‐499/Fnip1/AMPK circuit
Liu, J., Liang, X., Zhou, D., Lai, L., Xiao, L., Liu, L., Fu, T., Kong, Y., Zhou, Q., Vega, R. B., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606372 · Cited by 129 · see citing works
“H&E, SDH, and a-GPDH staining were performed as previously described (Zechner et al, 2010).”
InfluentialSelf-citationPGC-1α is Dispensable for Exercise-Induced Mitochondrial Biogenesis in Skeletal Muscle
Rowe, G. C., El‐Khoury, R., Patten, I. S., Rustin, P., & Arany, Z. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041817 · Cited by 127 · see citing works
“Whole body deletion and muscle-specific deletion of PGC-1a result in mild decrease in exercise performance [22,23,24].”
BackgroundSarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle
Maurya, S. K., Herrera, J. L., Sahoo, S. K., Reis, F. C. G., Vega, R. B., Kelly, D. P., & Periasamy, M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.036 · Cited by 129 · see citing works
“H&E, oil red O, SDH, and myosin heavy chain (MHC) staining were performed as previously described (Ahn et al., 2016; Gan et al., 2013; Jaspers et al., 2014; Zechner et al., 2010).”
MethodSelf-citationRedox basis of exercise physiology
Margaritelis, N. V., Paschalis, V., Theodorou, A. A., Kyparos, A., & Nikolaidis, M. G. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101499 · Cited by 129 · see citing works
Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies
Kubat, G. B., Bouhamida, E., Ülger, Ö., Türkel, İ., Pedriali, G., Ramaccini, D., Ekinci, Ö., Özerkliğ, B., Atalay, Ö., Patergnani, S., et al. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.07.003 · Cited by 128 · see citing works
The many roles of PGC-1α in muscle — recent developments
Chan, M. C., & Arany, Z. P. (2014) · Metabolism · doi:10.1016/j.metabol.2014.01.006 · Cited by 125 · see citing works
“Deletion of PGC-1α specifically in skeletal muscle has little effect on systemic glucose handling and insulin sensitivity [44], and deletion of PGC-1β specifically in skeletal muscle in the context of a whole-body PGC-1α hypomorphic allele (see above) similarly reveals few changes in glucose handling, despite profound…”
BackgroundMitochondrial Deficiency Is Associated With Insulin Resistance
Goodpaster, B. (2013) · Diabetes · doi:10.2337/db12-1612 · Cited by 123 · see citing works
“One of the arguments made that mitochondrial deficiency is disconnected from IR derives from either pathological conditions or genetic animal models of severe mitochondrial deficiency (18).”
BackgroundKruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation
Haldar, S. M., Jeyaraj, D., Anand, P., Zhu, H., Lu, Y., Prosdocimo, D. A., Eapen, B. L., Kawanami, D., Okutsu, M., Brotto, L. S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121060109 · Cited by 116 · see citing works
“Narkar VA, et al. (2011) Exercise and PGC-1α-independent synchronization of type I muscle metabolism and vasculature by ERRγ.”
BackgroundInfluentialSelf-citationPGC-1 coactivators in the cardiovascular system
Patten, I. S., & Arany, Z. P. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.007 · Cited by 119 · see citing works
Joseph, A.-M., Joanisse, D. R., Baillot, R. G., & Hood, D. A. (2011) · Experimental Diabetes Research · doi:10.1155/2012/642038 · Cited by 117 · see citing works
“In addition, several studies of muscle-specific PGC1α and/or PGC-1β null mice have demonstrated normal glucose tolerance and insulin sensitivity [47, 48].”
BackgroundSeparation of the gluconeogenic and mitochondrial functions of PGC-1α through S6 kinasePreprint
Lustig, Y., Ruas, J. L., Estall, J. L., Lo, J. C., Devarakonda, S., Laznik, D., Choi, J. H., Ono, H., Olsen, J. V., & Spiegelman, B. M. (2011) · Genes & Development · doi:10.1101/gad.2054711 · Cited by 115 · see citing works
“Mice lacking PGC-1a or PGC1b (or both) have a deficiency in mitochondria and adaptive oxidativemetabolism (Lin et al. 2004; Leone et al. 2005; Lelliott et al. 2006; Vianna et al. 2006; Zechner et al. 2010).”
BackgroundUpdate on mitochondria and muscle aging: All wrong roads lead to sarcopenia
Picca, A., Calvani, R., Bossola, M., Allocca, E., Menghi, A., Pesce, V., Lezza, A. M. S., Bernabei, R., Landi, F., & Marzetti, E. (2018) · Biological Chemistry · doi:10.1515/hsz-2017-0331 · Cited by 116 · see citing works
“Interestingly, muscle ablation of PGC-1α and 1β leads to substantial down-regulation of the gene expression of Mfn1, Mfn2, and Drp1 (Zechner et al., 2010).”
BackgroundInfluentialSestrins are evolutionarily conserved mediators of exercise benefits
Kim, M., Sujkowski, A. L., Namkoong, S., Gu, B., Cobb, T., Kim, B. Y., Kowalsky, A. H., Cho, C., Semple, I. A., Ro, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13442-5 · Cited by 116 · see citing works
The role of mitochondria in the aetiology of insulin resistance and type 2 diabetes
Martin, S. D., & McGee, S. L. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.09.019 · Cited by 112 · see citing works
Cho, Y., Hazen, B. C., Russell, A. P., & Kralli, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.489674 · Cited by 113 · see citing works
Sczelecki, S., Besse-Patin, A., Abboud, A., Kleiner, S., Laznik-Bogoslavski, D., Wrann, C. D., Ruas, J. L., Haibe-Kains, B., & Estall, J. L. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00578.2013 · Cited by 108 · see citing works
“Overexpression of PGC-1 in muscle protects aging mice from age-related muscle wasting and glucose intolerance (50, 52), and yet tight regulation of PGC-1 expression is required to maintain efficient glucose and lipid handling in obese mice (6, 19, 51).”
BackgroundResultInfluential“Deficiency” of Mitochondria in Muscle Does Not Cause Insulin Resistance
Holloszy, J. O. (2013) · Diabetes · doi:10.2337/db12-1107 · Cited by 111 · see citing works
“In a third study, Kelly and colleagues (31) generated mice that had combined deficiency of PGC-1a and PGC-1b in skeletal muscle.”
BackgroundRowe, G. C., Patten, I. S., Zsengellér, Z. K., El‐Khoury, R., Okutsu, M., Bampoh, S., Koulisis, N., Farrell, C., Hirshman, M. F., Yan, Z., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.023 · Cited by 104 · see citing works
“Zechner et al. (2010) recently generated mice in which PGC-1b is deleted in skeletal muscle and a hypomorphic allele of PGC-1a is present in all tissues.”
BackgroundMethodSelf-citationMelatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle
Teodoro, B. G., Baraldi, F. G., Sampaio, I. H., Bomfim, L. H. M., Queiroz, A. L., Passos, M. A., Carneiro, E. M., Alberici, L. C., Gomis, R., Amaral, F. G., et al. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12157 · Cited by 106 · see citing works
“The recovery of PGC-1 alpha by melatonin in the presence of palmitic acid could also play a role in the recovery of mitochondrial respiration because PGC-1 alpha promotes both oxidative phosphorylation-linked and uncoupling-linked respiration in differentiated myotubes oxidative capacity in skeletal muscle cells [21,…”
BackgroundExercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle
Liang, X., Liu, L., Fu, T., Zhou, Q., Zhou, D., Xiao, L., Liu, J., Kong, Y., Xie, H., Yi, F., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.749424 · Cited by 102 · see citing works
“SDH and immunofluorescence staining was performed as previously described (24).”
MethodSelf-citationRowe, G. C., Safdar, A., & Arany, Z. P. (2014) · Circulation · doi:10.1161/circulationaha.113.001590 · Cited by 104 · see citing works
“For example, genetic deletion of both PGC-1α and PGC-1β in murine muscle leaves the myofibers metabolically crippled but has almost no effect on the myofibrillar content of the myofibers.(45,46) The myofibrillar and metabolic responses to endurance exercise thus appear genetically dissociable and are likely regulated…”
Schirone, L., Forte, M., D’Ambrosio, L., Valenti, V., Vecchio, D., Schiavon, S., Spinosa, G., Sarto, G., Petrozza, V., Frati, G., et al. (2022) · Cells · doi:10.3390/cells11071165 · Cited by 104 · see citing works
The role of PGC‐1 coactivators in aging skeletal muscle and heart
Dillon, L. M., Rebelo, A. P., & Moraes, C. T. (2012) · IUBMB Life · doi:10.1002/iub.608 · Cited by 116 · see citing works
Wang, D., Sun, H., Song, G., Yang, Y., Zou, X., Han, P., & Li, S. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700941 · Cited by 102 · see citing works
Diop, S. B., Bisharat‐Kernizan, J., Birse, R. T., Oldham, S., Ocorr, K. A., & Bodmer, R. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.022 · Cited by 99 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript of metabolic adaptations (Arany, 2008; Baar et al., 2002; Goto et al., 2000; LeMoine et al., 2008; Tiefenbock et al., 2010; Tinkerhess et al., 2012; Zechner et al., 2010).”
PGC-1α Induces Human RPE Oxidative Metabolism and Antioxidant Capacity
Iacovelli, J., Rowe, G. C., Khadka, A., Diaz‐Aguilar, D., Spencer, C., Arany, Z. P., & Saint‐Geniez, M. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17758 · Cited by 97 · see citing works
Mitochondrial dynamics in cancer-induced cachexia
van der Ende, M., Grefte, S., Plas, R., Meijerink, J., Witkamp, R. F., Keijer, J., & van Norren, K. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.008 · Cited by 87 · see citing works
Cardiac adaptation to exercise training in health and disease
Seo, D. Y., Kwak, H., Kim, A. H., Park, S. H., Heo, J., Kim, H. K., Ko, J. R., Lee, S. J., Bang, H. S., Sim, J. W., et al. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-019-02266-3 · Cited by 91 · see citing works
Akasaki, Y., Ouchi, N., Izumiya, Y., Bernardo, B. L., LeBrasseur, N. K., & Walsh, K. (2013) · Aging Cell · doi:10.1111/acel.12153 · Cited by 88 · see citing works
“…that promotes mitochondrial biogenesis, a series of studies have reported mixed results regarding the involvement of oxidative muscle fibers in either metabolically challenged or aging mice (Benton et al., 2008; Choi et al., 2008; Wenz et al., 2009; Zechner et al., 2010; Finley et al., 2012).”
InfluentialCavaliere, G., Trinchese, G., Bergamo, P., De Filippo, C., Mattace Raso, G., Gifuni, G., Putti, R., Moni, B. H., Canani, R. B., Meli, R., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0149033 · Cited by 87 · see citing works
Halling, J. F., Ringholm, S., Olesen, J., Prats, C., & Pilegaard, H. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.05.020 · Cited by 86 · see citing works
“The importance of a well-balanced regulation of mitochondrial dynamics is highlighted by the findings that mice with tissue-specific deletion of MFN2 are glucose intolerant, insulin resistant and exhibit mitochondrial fragmentation and higher content of hydrogen peroxide in skeletal muscle (Sebastian et al., 2012).”
InfluentialMinetti, G., Feige, J. N., Rosenstiel, A., Bombard, F., Meier, V., Werner, A., Bassilana, F., Sailer, A. W., Kahle, P., Lambert, C., et al. (2011) · Science Signaling · doi:10.1126/scisignal.2002038 · Cited by 84 · see citing works
“Activity of the related PGC-1a mediates various protective effects in skeletal muscle, such as increasing the abundance of genes encoding neuromuscular junction proteins (50), maintaining mitochondria in aged animals, and blocking sarcopenia (30, 31, 51, 52).”
BackgroundFan, W., He, N., Lin, C. S., Wei, Z., Hah, N., Waizenegger, W., He, M.-X., Liddle, C., Yu, R. T., Atkins, A. R., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.047 · Cited by 85 · see citing works
“Severe defects in mitochondrial energetics were apparent in muscle from PKO mice, consistent with previous findings (Zechner et al., 2010).”
BackgroundResultInfluentialInvolvement of Mitochondrial Disorders in Septic Cardiomyopathy
Durand, A., Duburcq, T., Dekeyser, T., Nevière, R., Howsam, M., Favory, R., & Préau, S. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/4076348 · Cited by 84 · see citing works
“While insufficient biogenesis limits ATP production and induces cell necrosis [89], an excessive production of mitochondria leads to disruption of myofibrils and cardiomyocyte dysfunction [90].”
BackgroundAdiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice
Qiao, L., Yoo, H. S., Bosco, C., Lee, B., Feng, G., Schaack, J. B., Chi, N., & Shao, J. (2014) · Diabetologia · doi:10.1007/s00125-014-3180-5 · Cited by 83 · see citing works
“Mitochondrial respiration assay Mitochondria were purified from freshly collected tissues [23], and oxygen consumption was measured in a Mitocell Miniature respirometer (model 782, Strathkelvin Instruments Limited, Motherwell, UK) using pyruvate or palmitoyl-DL-carnitine (Sigma-Aldrich, St Louis, MO, USA) as substrate…”
MethodXu, Z., Fu, T., Guo, Q., Zhou, D., Sun, W., Zhou, Z., Chen, X., Zhang, J., Liu, L., Xiao, L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28557-5 · Cited by 82 · see citing works
Energy metabolism design of the striated muscle cell
Glancy, B. C., & Balaban, R. S. (2021) · Physiological Reviews · doi:10.1152/physrev.00040.2020 · Cited by 83 · see citing works
Rensvold, J. W., Ong, S.-E., Jeevananthan, A., Carr, S. A., Mootha, V. K., & Pagliarini, D. J. (2013) · Cell Reports · doi:10.1016/j.celrep.2012.11.029 · Cited by 82 · see citing works
“However, similar to PGC-1a / cells, depletion of PGC-1b expression in primary satellite cells isolated from soleus muscle of PGC-1b mice (Zechner et al., 2010) did not cause diminished levels of mitochondrial markers, nor did it alter the cellular response to DFO treatment (Figure 3G).”
PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training
Halling, J. F., Jessen, H., Nøhr-Meldgaard, J., Buch, B. T., Christensen, N. M., Gudiksen, A., Ringholm, S., Neufer, P. D., Prats, C., & Pilegaard, H. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00059.2019 · Cited by 82 · see citing works
Multiple Levels of PGC-1α Dysregulation in Heart Failure
Oka, S., Sabry, A. D., Cawley, K. M., & Warren, J. S. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00002 · Cited by 81 · see citing works
Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission
Green, A., Hossain, T., & Eckmann, D. M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1010232 · Cited by 83 · see citing works
Jaiswal, N., Gavin, M., Loro, E., Sostre‐Colón, J., Roberson, P. A., Uehara, K., Rivera‐Fuentes, N., Neinast, M., Arany, Z., Kimball, S. R., et al. (2022) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12846 · Cited by 79 · see citing works
Metabolic roles of PGC-1α and its implications for type 2 diabetes
Besseiche, A., Riveline, J., Gautier, J., Bréant, B., & Blondeau, B. (2015) · Diabetes & Metabolism · doi:10.1016/j.diabet.2015.02.002 · Cited by 80 · see citing works
“Although there are few data on the other two family memers, PGC-1 and PRC, and their roles, there may be redundancy etween PGC-1 and PGC-1 , despite other studies of PGCin skeletal muscles showing no involvement in either glucose omoeostasis or insulin sensitivity [86,87].”
BackgroundMetabolic control of myofibers: promising therapeutic target for obesity and type 2 diabetes
Duan, Y., Li, F., Tan, B., Yao, K., & Yin, Y. (2017) · Obesity Reviews · doi:10.1111/obr.12530 · Cited by 77 · see citing works
“Therefore, PGC-1 coactivators may be dispensable for fundamental fibre-type determination and insulin sensitivity (63).”
BackgroundTranscriptional Control of Cardiac Fuel Metabolism and Mitochondrial FunctionPreprint
Leone, T. C., & Kelly, D. P. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011965 · Cited by 77 · see citing works
“as described below, shares many if not all of its functions in striated muscle (Kelly and Scarpulla 2004; Lai et al. 2008; Zechner et al. 2010).”
BackgroundSelf-citationRamamoorthy, T. G., LAVERNY, G., Schlagowski, A.-I., Zoll, J., Messaddeq, N., Bornert, J., Panza, S., Ferry, A., Gény, B., & METZGER, D. (2015) · Nature Communications · doi:10.1038/ncomms10210 · Cited by 76 · see citing works
Trevino, M. B., Zhang, X., Standley, R. A., Wang, M., Han, X., Reis, F. C. G., Periasamy, M., Yu, G., Kelly, D. P., Goodpaster, B. H., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00161.2019 · Cited by 74 · see citing works
“These data are also in agreement with previous work by our group and others showing a severe exercise deficit in mice with loss of PGC-1 / in muscle (49, 68).”
ResultSelf-citationRahman, F. A., & Quadrilatero, J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03807-9 · Cited by 76 · see citing works
Gene Expression Profiling in Slow-Type Calf Soleus Muscle of 30 Days Space-Flown Mice
Gambara, G., Michele Salanova, A., Ciciliot, S., Furlan, S., Gutsmann, M., Schiffl, G., Ungethuem, U., Pompeo Volpe, D., Gunga, H., & Blottner, D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169314 · Cited by 74 · see citing works
“More recently, other laboratories demonstrated that the PGC-1 coactivators deficiency is crucial for exercise performance, mitochondrial structure and function, but surprisingly not for myofiber specification [37].”
Crupi, A. N., Nunnelee, J. S., Taylor, D. J., Thomas, A., Vit, J., Riera, C. E., Gottlieb, R. A., & Goodridge, H. S. (2018) · Aging · doi:10.18632/aging.101643 · Cited by 72 · see citing works
“Indeed, increased expression of PGC-1α and PGC-1β was previously shown to improve skeletal muscle health [19, 38-41].”
BackgroundMitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics
Affourtit, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.07.008 · Cited by 67 · see citing works
Rieusset, J. (2015) · Diabetes & Metabolism · doi:10.1016/j.diabet.2015.02.006 · Cited by 68 · see citing works
Research progress on the pharmacological effects of berberine targeting mitochondria
Fang, X., Wu, H., Wei, J., Miao, R., Zhang, Y., & Tian, J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.982145 · Cited by 72 · see citing works
“The research of transgenic animal experiments indicated that overexpression of PGC-1a, which regulates mitochondrial biosynthesis, resulted in increased oxidative phosphorylation protein expression in rat muscle tissue and palmitic acid oxidation, enhanced insulin sensitivity, increased insulinmediated glucose uptake,…”
Background
- Authors
- Zechner, C., Lai, L., Zechner, J. F., Geng, T., Yan, Z., Rumsey, J. W., Collia, D., Chen, Z., Wozniak, D. F., Leone, T. C., & Kelly, D. P.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of Virginia Medical Center (US)
- Washington University in St. Louis (US)
- Corresponding author
- Kelly, Daniel P.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 12
- Issue
- 6
- Pages
- 633-642
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2999961
- OpenAlex
- W2064754499
- Cited by
- 274
- References
- 45
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 11 · 2023: 12 · 2022: 19 · 2021: 13 · 2020: 13 · 2019: 19 · 2018: 19 · 2017: 21 · 2016: 23 · 2015: 22 · 2014: 12 · 2013: 31 · 2012: 16
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 959 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK45416, HL58427, P30 NS057105)
- American Diabetes Association (AR050429)
- Washington University School of Medicine in St. Louis
- Deutsche Forschungsgemeinschaft (ZE 796/2-1)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PGC-1α, PGC-1β, skeletal muscle, mitochondrial dysfunction, mitochondrial fission and fusion, oxidative capacity, muscle glycogen depletion, exercise performance, insulin sensitivity, glucose tolerance, muscle metabolism
- MeSH terms
- Analysis of Variance, Animals, Glucose Tolerance Test, Insulin Resistance, Microscopy, Electron, Mitochondria, Oxygen Consumption, Physical Conditioning, Animal, Transcription Factors, Polymerase Chain Reaction, Mice, Knockout, Muscle, Skeletal, Gene Expression Profiling, Mice
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