Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria
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PGC-1alpha overexpression in skeletal muscle, in vivo, has yielded disappointing and unexpected effects, including disrupted cellular integrity and insulin resistance. These unanticipated results may stem from an excessive PGC-1alpha overexpression in transgenic animals. Therefore, we examined the effects of a modest PGC-1alpha overexpression in a single rat muscle, in vivo, on fuel-handling proteins and insulin sensitivity. We also examined whether modest PGC-1alpha overexpression selectively targeted subsarcolemmal (SS) mitochondrial proteins and fatty acid oxidation, because SS mitochondria are metabolically more plastic than intermyofibrillar (IMF) mitochondria. Among metabolically heterogeneous rat hindlimb muscles, PGC-1alpha was highly correlated with their oxidative fiber content and with substrate transport proteins (GLUT4, FABPpm, and FAT/CD36) and mitochondrial proteins (COXIV and mTFA) but not with insulin-signaling proteins (phosphatidylinositol 3-kinase, IRS-1, and Akt2), nor with 5'-AMP-activated protein kinase, alpha2 subunit, and HSL. Transfection of PGC-1alpha into the red (RTA) and white tibialis anterior (WTA) compartments of the tibialis anterior muscle increased PGC-1alpha protein by 23-25%. This also induced the up-regulation of transport proteins (FAT/CD36, 35-195%; GLUT4, 20-32%) and 5'-AMP-activated protein kinase, alpha2 subunit (37-48%), but not other proteins (FABPpm, IRS-1, phosphatidylinositol 3-kinase, Akt2, and HSL). SS and IMF mitochondrial proteins were also up-regulated, including COXIV (15-75%), FAT/CD36 (17-30%), and mTFA (15-85%). PGC-1alpha overexpression also increased palmitate oxidation in SS (RTA, +116%; WTA, +40%) but not in IMF mitochondria, and increased insulin-stimulated phosphorylation of AKT2 (28-43%) and rates of glucose transport (RTA, +20%; WTA, +38%). Thus, in skeletal muscle in vivo, a modest PGC-1alpha overexpression up-regulated selected plasmalemmal and mitochondrial fuel-handling proteins, increased SS (not IMF) mitochondrial fatty acid oxidation, and improved insulin sensitivity.
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PGC-1α overexpression in mouse skeletal muscle enhanced mitochondrial activity, increased expression of proteins involved in fat oxidation and glucose transport, and increased insulin-stimulated glucose uptake by about 35%.
“Over expression of the PGC-1 alpha gene in skeletal muscle in mice in vivo enhanced mitochondrial activity, augmented the expression of multiple proteins involved in fat oxidation and glucose transport, and increased by ~35% insulin-stimulated glucose uptake [133].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [133]
The lowest level of PGC-1α overexpression in rat muscle by electroporation resulted in modest up-regulation of mitochondrial proteins, increased palmitate oxidation, and increased insulin-stimulated glucose uptake.
“The lowest level of PGC-1␣ overexpression was achieved in rat muscle by means of electroporation (261).This resulted in modest up-regulation of mitochondrial proteins, increased palmitate oxidation, and increased insulin-stimulated glucose uptake.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [261]
Modest overexpression of PGC-1α and transgenic overexpression of PGC-1β increase oxidative metabolism and insulin sensitivity.
“Taken together, these studies suggest that modest overexpression of PGC-1␣ (261, 262) and transgenic overexpression of PGC-1 (271, 272) increase oxidative metabolism and insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [261]
PGC-1α transgenic expression increases OXPHOS mRNA and protein levels, with increases ranging from 130% to 500% across transgenic models.
“180% 1 COXIV | protein | 130% 1 mRNA | | 150 -200% | 1 mRNA | | | 150 -250% | 1 mRNA | | | | 170 -300% | 1 mRNA | 200 -500% | 1 mRNA and | protein”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [261]
PGC-1α electroporation in muscle increased mitochondrial DNA by 113% (Benton, 2008).
“Mito DNA | 1 113%”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [261]
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References 63 · Cited by 214
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- Authors
- Benton, C. R., Nickerson, J. G., Lally, J., Han, X.-X., Holloway, G. P., Glatz, J. F. C., Luiken, J. J. F. P., Graham, T. E., Heikkila, J. J., & Bonen, A.
- Affiliations
- University of Waterloo (CA)
- University of Guelph (CA)
- Maastricht University (NL)
- Corresponding author
- Bonen, Arend
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 283
- Issue
- 7
- Pages
- 4228-4240
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2116242674
- Cited by
- 214
- References
- 63
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 7 · 2021: 2 · 2020: 4 · 2019: 7 · 2018: 9 · 2017: 13 · 2016: 8 · 2015: 15 · 2014: 13 · 2013: 13 · 2012: 16
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- PGC-1α, skeletal muscle, insulin sensitivity, palmitate oxidation, subsarcolemmal mitochondria, interfibrillar mitochondria, fatty acid oxidation, GLUT4, FAT/CD36, AMPK, Akt2 phosphorylation, glucose transport, tibialis anterior, transgenic overexpression
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Base Sequence, Biological Transport, Fatty Acids, Glucose, Insulin, Male, Mitochondria, Muscle, Oxidation-Reduction, Phosphorylation, Transcription Factors, RNA-Binding Proteins, Rats, Sprague-Dawley, DNA Primers, Muscle, Skeletal, Palmitic Acid, Proto-Oncogene Proteins c-akt, Rats
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