Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle
Open accessAbstract
TBC1D1 is a Rab-GTPase-activating protein (GAP) known to be phosphorylated in response to insulin, growth factors, pharmacological agonists that activate 5'-AMP-activated protein kinase (AMPK), and muscle contraction. Silencing TBC1D1 in L6 muscle cells by siRNA increases insulin-stimulated GLUT4 translocation, and overexpression of TBC1D1 in 3T3-L1 adipocytes with low endogenous TBC1D1 expression inhibits insulin-stimulated GLUT4 translocation, suggesting a role of TBC1D1 in regulating GLUT4 translocation. Aiming to unravel the regulation of TBC1D1 during contraction and the potential role of AMPK in intact skeletal muscle, we used EDL muscles from wild-type (WT) and AMPK kinase dead (KD) mice. We explored the site-specific phosphorylation of TBC1D1 Ser(237) and Thr(596) and their relation to 14-3-3 binding, a proposed mechanism for regulation of GAP function of TBC1D1. We show that muscle contraction increases 14-3-3 binding to TBC1D1 as well as phosphorylation of Ser(237) and Thr(596) in an AMPK-dependent manner. AMPK activation by AICAR induced similar Ser(237) and Thr(596) phosphorylation of, and 14-3-3 binding to, TBC1D1 as muscle contraction. Insulin did not increase Ser(237) phosphorylation or 14-3-3 binding to TBC1D1. However, insulin increased Thr(596) phosphorylation, and intriguingly this response was fully abolished in the AMPK KD mice. Thus, TBC1D1 is differentially regulated in response to insulin and contraction. This study provides genetic evidence to support an important role for AMPK in regulating TBC1D1 in response to both of these physiological stimuli.
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Exercise-induced AMPK is thought to phosphorylate and inhibit the Rab-GAP proteins TBC1D1/TBC1D4.
“In addition to this event exercise induced AMPK is also thought to phosphorylate and inhibit the Rab-GAP proteins TBC1D1/TBC1D4 [16][17][18].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [16]
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 [74]
Insulin does not increase AMPK T172 or ACC S79/212 phosphorylation.
“In support of this, insulin also does not increase AMPK T172 or ACC S79/212 phosphorylation [74] and AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle [26,28,30,36,100] despite blunted TBC1D1 PAS and T590 phosphorylation in response to insulin [30,74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D4 phosphorylation at T642 is the predominant Akt site recognized by the PAS antibody.
“Correlation studies suggest that T642 (human and T649 in mouse) is the predominant Akt site on TBC1D4 recognized by the PAS antibody [74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D1 expression is reduced by ~50% in skeletal muscle of AMPK α2 KO, α2 KD, α2iTg and β1β2 M-KO mice.
“In contrast, TBC1D1 expression is reduced by ~50% in skeletal muscle of AMPK α2 KO, α2 KD, α2iTg and β1β2 M-KO mice [30,74,102,117], and this may be compensatory for the lack of phosphorylation and inhibition by AMPK, or alternatively, reduced muscle glucose uptake in AMPK β1β2 M-KO mice.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
Phosphorylation of TBC1D1 at S237 appears to be the predominant site phosphorylated by AMPK; however, TBC1D1 PAS phosphorylation does not appear to correlate well with S237 phosphorylation.
“Phosphorylation of TBC1D1 at S237 appears to be the predominant site phosphorylated by AMPK; however, TBC1D1 PAS phosphorylation does not appear to correlate well with S237 phosphorylation [74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
Muscle contractions/exercise predominantly induces TBC1D1 phosphorylation on S231 in both humans and mice.
“AMPK phosphorylates multiple sites on TBC1D1 (S231, S499, T590, S660, S700), and muscle contractions/exercise predominately induces TBC1D1 phosphorylation on S231 in both humans and mice [74,102,117].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D1 requires 14-3-3 binding in response to contraction and AICAR but not insulin in both human and rodent skeletal muscle.
“Unlike TBC1D4, TBC1D1 requires 14-3-3 binding in response to contraction and AICAR but not insulin in both human and rodent skeletal muscle [74,117].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions.
“TBC1D1 PAS phosphorylation is slightly increased in α2iTg and α2KO mice but unresponsive in AMPK KD and β1β2 M-KO mice following contractions [30,74], suggesting that AMPK is important for PAS phosphorylation in response to contraction.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D1 phosphorylation is enhanced immediately following exercise but returns to basal levels 3-4 and 27 hours post-exercise in rats.
“TBC1D1 phosphorylation is enhanced immediately following exercise but returns to basal levels 3-4 and 27 hours post-exercise in rats, suggesting that the involvement of TBC1D1 in the insulin sensitizing effects of exercise are different from that of TBC1D4.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
TBC1D1 T590 is predominantly phosphorylated in response to muscle contractions, but this has not been observed in all studies.
“TBC1D1 T590 is also predominately phosphorylated in response to muscle contractions [74]; however, this has not been observed in all studies [102].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
AMPK phosphorylates multiple sites on TBC1D1 (S231, S499, T590, S660, S700).
“AMPK phosphorylates multiple sites on TBC1D1 (S231, S499, T590, S660, S700), and muscle contractions/exercise predominately induces TBC1D1 phosphorylation on S231 in both humans and mice [74,102,117].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [74]
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Self-citation
- Authors
- Pehmøller, C., Treebak, J. T., Birk, J. B., Chen, S., MacKintosh, C., Hardie, D. G., Richter, E. A., & Wojtaszewski, J. F. P.
- Affiliations
- University of Copenhagen (DK)
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-09
- Volume
- 297
- Issue
- 3
- Pages
- E665-E675
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC2739697
- OpenAlex
- W2167698452
- Cited by
- 171
- References
- 33
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 14 · 2018: 11 · 2017: 7 · 2016: 17 · 2015: 13 · 2014: 17 · 2013: 18 · 2012: 8
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- TBC1D1, AMPK signaling, skeletal muscle, muscle contraction, insulin signaling, 14-3-3 binding, protein phosphorylation, Rab GTPase-activating protein, GLUT4 translocation, AICAR, EDL muscle
- MeSH terms
- Animals, Female, Insulin, Mice, Inbred C57BL, Mice, Transgenic, Muscle Contraction, Nuclear Proteins, Phosphorylation, Protein Binding, Signal Transduction, Mutagenesis, Protein Serine-Threonine Kinases, Muscle, Skeletal, GTPase-Activating Proteins, 14-3-3 Proteins, Mice, AMP-Activated Protein Kinases
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