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

Abstract

ObjectiveA 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.MethodsWe 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.ResultsSustained 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.ConclusionOur 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.

Exercise training reduces the insulin‐sensitizing effect of a single bout of exercise in human skeletal muscle

“…Thus, the level of phosphorylation of the equivalent TBC1D4 Ser704 (in humans) is associated with AMPKα 2 β 2 γ 3 activity during exercise in samples of whole muscle as well as in samples representing either type I or type II muscle fibres (Kristensen et al 2015). Also, we recently reported enhanced phosphor-regulation of TBC1D4 by insulin concomitantly with enhanced insulin-stimulated glucose uptake following exercise (Treebak et al 2009;Pehmøller et al 2012;Sjøberg et al 2017;Hingst et al 2018). In the present study, we found reduced phosphorylation of TBC1D4 Ser704/Thr642 4 h after exercise in the acutely exercised leg after training compared to before training, whereas phosphorylation of TBC1D4 Ser704/Thr642 during insulin stimulation reached similar levels before and after training.…”

“…; Hingst et al . ). In the present study, we found reduced phosphorylation of TBC1D4 Ser704/Thr642 4 h after exercise in the acutely exercised leg after training compared to before training, whereas phosphorylation of TBC1D4 Ser704/Thr642 during insulin stimulation reached similar levels before and after training.…”

The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery

“…Together these data implicate that AMPK is important in partitioning glucose for muscle glycogen resynthesis rather than oxidation during recovery. Even more directly, it was recently shown in a muscle-specific, inducible AMPK catalytic isoform KO mouse model (AMPKα1/α2 imdKO) that muscle glycogen synthesis was markedly reduced when glucose was administered orally following exercise [82]. Furthermore, AMPK was recently shown to be important for muscle basal glucose uptake [83] and insulin-stimulated glucose uptake [84] in mice following muscle contractions and in vivo exercise via regulation of TBC1D1 [83] and TBC1D4 [85], respectively.…”

Increase in Subcellular GSK-3 Clusters in Insulin- and Adrenaline-treated Differentiated Rat Skeletal Muscle Fibres

“…On the other hand, insulin dependent signalling phosphorylates GSK-3 and activates GS (Bouskila et al, 2008). Hence glycogen is essential in body glucose metabolism, specifically in skeletal muscle, where exercise induces insulin sensitization and enhances glucose uptake in part to enable glycogen supercompensation in the post exercise period (Hingst et al, 2018). This is due to increased sensitivity of muscle to insulin and higher GS activity during and after exercise (Hingst et al, 2018).…”

“…Hence glycogen is essential in body glucose metabolism, specifically in skeletal muscle, where exercise induces insulin sensitization and enhances glucose uptake in part to enable glycogen supercompensation in the post exercise period (Hingst et al, 2018). This is due to increased sensitivity of muscle to insulin and higher GS activity during and after exercise (Hingst et al, 2018). Importantly, the individual responses generated by insulin and adrenaline do not predict the responses that will be generated by combined stimulation with these agonists (Jensen et al, 2007).…”