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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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“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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Martin, S. D., & McGee, S. L. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.09.019 · Cited by 117
Cho, Y., Hazen, B. C., Russell, A. P., & Kralli, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.489674 · Cited by 117
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
“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
“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 106
“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
“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 105
“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 107
“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 111
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
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
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 101
“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 100
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
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
Akasaki, Y., Ouchi, N., Izumiya, Y., Bernardo, B. L., LeBrasseur, N. K., & Walsh, K. X. (2013) · Aging Cell · doi:10.1111/acel.12153 · Cited by 93
“…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
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
“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 87
“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 89
“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 85
“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 80
“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
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 86
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
“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 83
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 85
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 86
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
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 84
“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 81
“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
“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 82
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 73
“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 77
Gene Expression Profiling in Slow-Type Calf Soleus Muscle of 30 Days Space-Flown Mice
Gambara, G., Salanova, M., Ciciliot, S., Furlan, S., Gutsmann, M., Schiffl, G., Ungethuem, U., Volpe, P., Gunga, H., & Blottner, D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169314 · Cited by 78
“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
“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
Rieusset, J. (2015) · Diabetes & Metabolism · doi:10.1016/j.diabet.2015.02.006 · Cited by 69
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 75
“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
Metadata
- 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 (medical) › 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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