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Cited by 73Metabolism, Diabetes, and CancerMuscle metabolism and nutritionCardiovascular and exercise physiology

Exercise‐induced TBC1D1 Ser237 phosphorylation and 14‐3‐3 protein binding capacity in human skeletal muscle

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Frøsig, Christian, Pehmøller, Christian, Birk, Jesper B., Richter, Erik A., Wojtaszewski, Jørgen F. P.·2010·The Journal of Physiology
DOI 10.1113/jphysiol.2010.194811PMC PMC3008856
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Abstract

TBC1D1 is a Rab‐GTPase activating protein involved in regulation of GLUT4 translocation in skeletal muscle. We here evaluated exercise‐induced regulation of TBC1D1 Ser237 phosphorylation and 14‐3‐3 protein binding capacity in human skeletal muscle. In separate experiments healthy men performed all‐out cycle exercise lasting either 30 s, 2 min or 20 min. After all exercise protocols, TBC1D1 Ser237 phosphorylation increased (∼70–230%, P < 0.005), with the greatest response observed after 20 min of cycling. Interestingly, capacity of TBC1D1 to bind 14‐3‐3 protein showed a similar pattern of regulation, increasing 60–250% (P < 0.001). Furthermore, recombinant 5′AMP‐activated protein kinase (AMPK) induced both Ser237 phosphorylation and 14‐3‐3 binding properties on human TBC1D1 when evaluated in vitro. To further characterize the role of AMPK as an upstream kinase regulating TBC1D1, extensor digitorum longus muscle (EDL) from whole body α1 or α2 AMPK knock‐out and wild‐type mice were stimulated to contract in vitro. In wild‐type and α1 knock‐out mice, contractions resulted in a similar ∼100% increase (P < 0.001) in Ser237 phosphorylation. Interestingly, muscle of α2 knock‐out mice were characterized by reduced protein content of TBC1D1 (∼50%, P < 0.001) as well as in basal and contraction‐stimulated (∼60%, P < 0.001) Ser237 phosphorylation, even after correction for the reduced TBC1D1 protein content. This study shows that TBC1D1 is Ser237 phosphorylated and 14‐3‐3 protein binding capacity is increased in response to exercise in human skeletal muscle. Furthermore, we show that the catalytic α2 AMPK subunit is the main (but probably not the only) donor of AMPK activity regulating TBC1D1 Ser237 phosphorylation in mouse EDL muscle.

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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 [117]

  • 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 [117]

  • 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 [117]

  • 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 [117]

  • 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 [117]

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Authors
Frøsig, C., Pehmøller, C., Birk, J. B., Richter, E. A., & Wojtaszewski, J. F. P.
Affiliations
University of Copenhagen (DK)
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2010-11-15
Volume
588
Issue
22
Pages
4539-4548
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jphysiol.2010.194811
PMC
PMC3008856
OpenAlex
W1596136472
Cited by
73
References
34
Citations by year
2025: 3 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 8 · 2012: 8
FWCI
2.86
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
TBC1D1, 14-3-3 protein binding, Rab GTPase-activating protein, skeletal muscle, physical activity, AMPK, GLUT4 translocation, extensor digitorum longus, muscle contraction
MeSH terms
Adult, Animals, Catalysis, Female, Humans, Male, Mice, Inbred C57BL, Nuclear Proteins, Phosphorylation, Protein Binding, Serine, Species Specificity, Exercise, Up-Regulation, Mice, Knockout, Muscle, Skeletal, GTPase-Activating Proteins, 14-3-3 Proteins, Mice, AMP-Activated Protein Kinases

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