Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle

Janne Rasmuss Hingst; Lea Bruhn; Mads B Hansen; Marie F Rosschou; Jesper Bratz Birk; Joachim Fentz; Marc Foretz; Benoit Viollet; Kei Sakamoto; Nils J Færgeman; Jesper F Havelund; Benjamin L Parker; David E James; Bente Kiens; Erik Richter; Jørgen Jensen; Jørgen Wojtaszewski

doi:10.1016/j.molmet.2018.07.001

Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle

Janne Rasmuss Hingst, Lea Bruhn, Mads B Hansen, Marie F Rosschou, Jesper Bratz Birk, Joachim Fentz, Marc Foretz, Benoit Viollet, Kei Sakamoto, Nils J Færgeman, Jesper F Havelund, Benjamin L Parker, David E James, Bente Kiens, Erik Richter, Jørgen Jensen, Jørgen Wojtaszewski^*

^*Corresponding author for this work

The August Krogh Section for Molecular Physiology

22 Citations (Scopus)

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Abstract

Objective: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man.

Methods: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control. Euglycemic hyperinsulinemic clamps in combination with leg balance technique allowed for investigating insulin-stimulated leg glucose uptake under these 3 experimental conditions. Cellular signaling in muscle biopsies was investigated by global proteomic analyses and immunoblotting. We strengthened the validity of proposed molecular effectors by follow-up studies in muscle of transgenic mice.

Results: Sustained activation of glycogen synthase (GS) and AMPK in combination with elevated expression of proteins determining glucose uptake capacity were evident in the prior exercised muscle. We hypothesize that these alterations offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen. In line with key roles of AMPK and GS seen in the human experiments we observed abrogated ability for glycogen supercompensation in muscle with inducible AMPK deletion and in muscle carrying a G6P-insensitive form of GS in muscle.

Conclusion: Our study demonstrates that both AMPK and GS are key regulators of glycogen supercompensation following a single bout of glycogen-depleting exercise in skeletal muscle of both man and mouse.

Original language	English
Journal	Molecular Metabolism
Volume	16
Pages (from-to)	24-34
Number of pages	11
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2018.07.001
Publication status	Published - Oct 2018

Keywords

AMP-activated protein kinase (AMPK)
Exercise
Glucose uptake
Glycogen synthase (GS)
Insulin action
TBC1 domain family member 4 (TBC1D4)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hingst, J. R., Bruhn, L., Hansen, M. B., Rosschou, M. F., Birk, J. B., Fentz, J., Foretz, M., Viollet, B., Sakamoto, K., Færgeman, N. J., Havelund, J. F., Parker, B. L., James, D. E., Kiens, B., Richter, E., Jensen, J., & Wojtaszewski, J. (2018). Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle. Molecular Metabolism, 16, 24-34. https://doi.org/10.1016/j.molmet.2018.07.001

Hingst, JR, Bruhn, L, Hansen, MB, Rosschou, MF, Birk, JB, Fentz, J, Foretz, M, Viollet, B, Sakamoto, K, Færgeman, NJ, Havelund, JF, Parker, BL, James, DE, Kiens, B , Richter, E, Jensen, J & Wojtaszewski, J 2018, 'Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle', Molecular Metabolism, vol. 16, pp. 24-34. https://doi.org/10.1016/j.molmet.2018.07.001

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abstract = "Objective: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man. Methods: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control. Euglycemic hyperinsulinemic clamps in combination with leg balance technique allowed for investigating insulin-stimulated leg glucose uptake under these 3 experimental conditions. Cellular signaling in muscle biopsies was investigated by global proteomic analyses and immunoblotting. We strengthened the validity of proposed molecular effectors by follow-up studies in muscle of transgenic mice. Results: Sustained activation of glycogen synthase (GS) and AMPK in combination with elevated expression of proteins determining glucose uptake capacity were evident in the prior exercised muscle. We hypothesize that these alterations offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen. In line with key roles of AMPK and GS seen in the human experiments we observed abrogated ability for glycogen supercompensation in muscle with inducible AMPK deletion and in muscle carrying a G6P-insensitive form of GS in muscle. Conclusion: Our study demonstrates that both AMPK and GS are key regulators of glycogen supercompensation following a single bout of glycogen-depleting exercise in skeletal muscle of both man and mouse.",

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doi = "10.1016/j.molmet.2018.07.001",

language = "English",

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T1 - Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle

AU - Hingst, Janne Rasmuss

AU - Bruhn, Lea

AU - Hansen, Mads B

AU - Rosschou, Marie F

AU - Birk, Jesper Bratz

AU - Fentz, Joachim

AU - Foretz, Marc

AU - Viollet, Benoit

AU - Sakamoto, Kei

AU - Færgeman, Nils J

AU - Havelund, Jesper F

AU - Parker, Benjamin L

AU - James, David E

AU - Kiens, Bente

AU - Richter, Erik

AU - Jensen, Jørgen

AU - Wojtaszewski, Jørgen

N1 - CURIS 2018 NEXS 269

PY - 2018/10

Y1 - 2018/10

N2 - Objective: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man. Methods: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control. Euglycemic hyperinsulinemic clamps in combination with leg balance technique allowed for investigating insulin-stimulated leg glucose uptake under these 3 experimental conditions. Cellular signaling in muscle biopsies was investigated by global proteomic analyses and immunoblotting. We strengthened the validity of proposed molecular effectors by follow-up studies in muscle of transgenic mice. Results: Sustained activation of glycogen synthase (GS) and AMPK in combination with elevated expression of proteins determining glucose uptake capacity were evident in the prior exercised muscle. We hypothesize that these alterations offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen. In line with key roles of AMPK and GS seen in the human experiments we observed abrogated ability for glycogen supercompensation in muscle with inducible AMPK deletion and in muscle carrying a G6P-insensitive form of GS in muscle. Conclusion: Our study demonstrates that both AMPK and GS are key regulators of glycogen supercompensation following a single bout of glycogen-depleting exercise in skeletal muscle of both man and mouse.

AB - Objective: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man. Methods: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control. Euglycemic hyperinsulinemic clamps in combination with leg balance technique allowed for investigating insulin-stimulated leg glucose uptake under these 3 experimental conditions. Cellular signaling in muscle biopsies was investigated by global proteomic analyses and immunoblotting. We strengthened the validity of proposed molecular effectors by follow-up studies in muscle of transgenic mice. Results: Sustained activation of glycogen synthase (GS) and AMPK in combination with elevated expression of proteins determining glucose uptake capacity were evident in the prior exercised muscle. We hypothesize that these alterations offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen. In line with key roles of AMPK and GS seen in the human experiments we observed abrogated ability for glycogen supercompensation in muscle with inducible AMPK deletion and in muscle carrying a G6P-insensitive form of GS in muscle. Conclusion: Our study demonstrates that both AMPK and GS are key regulators of glycogen supercompensation following a single bout of glycogen-depleting exercise in skeletal muscle of both man and mouse.

KW - AMP-activated protein kinase (AMPK)

KW - Exercise

KW - Glucose uptake

KW - Glycogen synthase (GS)

KW - Insulin action

KW - TBC1 domain family member 4 (TBC1D4)

U2 - 10.1016/j.molmet.2018.07.001

DO - 10.1016/j.molmet.2018.07.001

M3 - Journal article

C2 - 30093357

AN - SCOPUS:85050996496

SN - 2212-8778

VL - 16

SP - 24

EP - 34

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -

Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle

Abstract

Keywords

UN SDGs

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