Inhibition of Contraction-Stimulated AMP-Activated Protein Kinase Inhibits Contraction-Stimulated Increases in PAS-TBC1D1 and Glucose Transport Without Altering PAS-AS160 in Rat Skeletal Muscle
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OBJECTIVE: Phosphorylation of two members of the TBC1 domain family of proteins, Akt substrate of 160 kDa (AS160, also known as TBC1D4) and TBC1D1, has been implicated in the regulation of glucose transport in skeletal muscle. Insulin-stimulated phosphorylation (measured using the phospho-Akt substrate [PAS] antibody) of AS160 and TBC1D1 appears to occur in an Akt-dependent manner, but the kinases responsible for contraction-stimulated PAS-AS160 and PAS-TBC1D1 remain unclear. AMP-activated protein kinase (AMPK) and Akt, both activated by contraction, can each phosphorylate AS160 and TBC1D1 in cell-free assays. RESEARCH DESIGN AND METHODS: To evaluate the roles of AMPK and Akt on insulin- or contraction-stimulated PAS-AS160, PAS-TBC1D1, and glucose transport, rat epitrochlearis was incubated with and without compound C (inhibitor of AMPK) or Wortmannin (inhibitor of phosphatidylinositol [PI] 3-kinase, which is upstream of Akt) before and during insulin stimulation or contraction. RESULTS: Insulin-stimulated glucose transport and phosphorylation of both AS160 and TBC1D1 were completely inhibited by Wortmannin. Wortmannin eliminated contraction stimulation of phospho-Ser21/9glycogen synthase kinase 3α/β (pGSK3; Akt substrate) and PAS-AS160 but did not significantly alter pAMPK, phospho-Ser79acetyl CoA carboxylase (pACC; AMPK substrate), PAS-TBC1D1, or glucose transport in contraction-stimulated muscle. Compound C completely inhibited contraction-stimulated pACC and PAS-TBC1D1 and partially blocked glucose transport, but it did not significantly alter pAkt, pGSK3, or PAS-AS160. CONCLUSIONS: These data suggest that 1) insulin stimulates glucose transport and phosphorylation of AS160 and TBC1D1 in a PI 3-kinase/Akt–dependent manner, 2) contraction stimulates PAS-AS160 (but not PAS-TBC1D1 or glucose transport) in a PI 3-kinase/Akt–dependent manner, and 3) contraction stimulates PAS-TBC1D1 and glucose transport (but not PAS-AS160) in an AMPK-dependent manner.
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TBC1D1 is phosphorylated in response to AICAR and muscle contractions/exercise.
“Like TBC1D4, TBC1D1 is phosphorylated in response to AICAR and muscle contractions/exercise [74,95,101,102,117].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [101]
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References 53 · Cited by 76
- Authors
- Funai, K., & Cartee, G. D.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Cartee, Gregory D.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2009-02-10
- Volume
- 58
- Issue
- 5
- Pages
- 1096-1104
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2671042
- OpenAlex
- W2131356526
- Cited by
- 76
- References
- 53
- Citations by year
- 2026: 1 · 2022: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 10 · 2013: 7 · 2012: 8
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (AG-010026)
- National Institute on Aging (AG010026, R01AG010026)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK071771, R01DK071771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- AMPK, AS160, TBC1D1, TBC1D4, glucose transport, skeletal muscle, muscle contraction, insulin signaling, PI3K/Akt signaling, glycogen synthase kinase-3, acetyl-CoA carboxylase, compound C, wortmannin, GLUT4 translocation
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Enzyme Inhibitors, Glucose, Humans, Insulin, Male, Muscle Contraction, Nuclear Proteins, Recombinant Proteins, 3T3 Cells, Rats, Wistar, Adipocytes, Muscle, Skeletal, GTPase-Activating Proteins, Mice, Rats, AMP-Activated Protein Kinases
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