American Diabetes Association
Online-only_supplementary_materials_Kido_et_al_clean_copy.pdf (294.17 kB)

AMPKγ3 controls muscle glucose uptake in recovery from exercise to recapture energy stores

Download (294.17 kB)
posted on 2023-07-28, 19:43 authored by Kohei Kido, Nicolas O. Eskesen, Nicolai S. Henriksen, Johan Onslev, Jonas M. Kristensen, Magnus R. Larsen, Janne R. Hingst, Jonas. R. Knudsen, Jesper B. Birk, Nicoline R. Andersen, Thomas E. Jensen, Christian Pehmøller, Jørgen F.P. Wojtaszewski, Rasmus Kjøbsted

Exercise increases muscle glucose uptake independently of insulin signaling and represents a cornerstone for the prevention of metabolic disorders. Pharmacological activation of the exercise-responsive AMPK in skeletal muscle has been proven successful as a therapeutic approach to treat metabolic disorders by improving glucose homeostasis through the regulation of muscle glucose uptake. However, conflicting observations cloud the proposed role of AMPK as a necessary regulator of muscle glucose uptake during exercise. We show that glucose uptake increases in human skeletal muscle in the absence of AMPK activation during exercise and that exercise-stimulated AMPKγ3 activity strongly correlates to muscle glucose uptake in the post-exercise period. In AMPKγ3-deficient mice, muscle glucose uptake is normally regulated during exercise and contractions but impaired in the recovery period from these stimuli. Impaired glucose uptake in recovery from exercise and contractions is associated to a lower glucose extraction, which can be explained by a diminished permeability to glucose and abundance of glucose transporter 4 (GLUT4) at the muscle plasma membrane. As a result, AMPKγ3-deficiency impairs muscle glycogen resynthesis following exercise. These results identify a physiological function of the AMPKγ3 complex in human and rodent skeletal muscle that serves to regulate glucose uptake in recovery from exercise to recapture muscle energy stores.


Funding for the study was provided by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406 (to RK). Further funding for the study was provided by grants from the Danish Council for Independent Research (FSS: 8020-00288B) (to JFPW), the Novo Nordisk Foundation (NNF21OC0070370) (to JFPW), the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, grant number 19K20007 (to KK) and the EFSD/JDS Fellowship Program (to KK). None of the funding agencies had any role in the study design or in the collection and interpretation of the data.