Cited by 214Adipose Tissue and MetabolismMetabolism, Diabetes, and CancerMuscle Physiology and Disorders

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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Benton, Carley R., Nickerson, James G., Lally, James, Han, Xiao-Xia, Holloway, Graham P., Glatz, Jan F.C., Luiken, Joost J. F.P., Graham, Terry E. +2 more·2008·Journal of Biological Chemistry

Abstract

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.”
  • 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.”
  • 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”
  • PGC-1α electroporation in muscle increased mitochondrial DNA by 113% (Benton, 2008).

    “Mito DNA | 1 113%”

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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
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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