Poster Presentation 12th International Meeting on AMPK 2023

mTORC1 may inhibit AMPK a2b2g3 by phosphorylation of a2 ser345 and ser377 to suppress the insulin-sensitizing effect of exercise in humans (#71)

Magnus Romme Leandersson 1 , Johan Dejgaard Onslev 1 , Nicolai Stevns Henriksen 1 , Magnus Narud Zankel 1 , Jonas Møller Kristensen 1 , Jørgen Frank Pind Wojtaszewski 1
  1. University of Copenhagen, Copenhagen, Denmark

mTORC1 directly phosphorylate AMPKa2 at ser345 (Morrison et al. 2022; Ling et al. 2020) and ser377 (Needham et al. 2022). The AMPK a2b2g3 complex improves skeletal muscle insulin sensitivity following exercise, but paradoxically, the activity of this complex may be suppressed by insulin in recovery from exercise (Hingst et al. 2018). Notably, mTORC1 is highly activated by insulin in recovery from exercise (Needham et al. 2022). We speculate, that mTORC1 acts in a negative feedback loop to dampen the insulin-sensitizing effect of exercise. Therefore, we hypothesized, that pharmacological inhibition of mTORC1 would enhance the insulin-sensitizing effect of exercise in humans. To test this, we included 13 young healthy males in a crossover blinded study administering Rapamycin or placebo followed by one-legged knee extensor exercise, exercise recovery and a hyperinsulinemic euglycemic clamp. The primary outcome was leg glucose uptake, assessed by Fick’s principle, in the previously exercising leg as well as the resting control leg. Rapamycin administration did not impact leg glucose uptake during exercise, in exercise recovery nor in the rested control leg following insulin stimulation. However, Rapamycin did improve the insulin-sensitizing effect of exercise by ~32% (p=0.049). These data could suggest that ablating the negative feedback loop of the mTORC1-AMPK interaction enhances muscle insulin sensitivity following exercise. Upcoming analyses from this study will include activity of the AMPK a2b2g3 complex during exercise, in exercise recovery and following the insulin clamp.

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