Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle
Abstract
Objective Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle. Methods Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1 -/- /γ3 -/- ) and single knockout (imγ1⁻ / ⁻ and imγ3⁻ / ⁻) mice were generated . Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed. Results snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo , glucose uptake stimulated by either AICAR or MK-8722 was abolished in imγ1⁻ / ⁻/γ3⁻ / ⁻ muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo . AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3⁻ / ⁻, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1⁻ / ⁻ mice. Conclusions While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
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BibTeX
@article{biswas2026common,
title = {{Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle}},
author = {Dipsikha Biswas and Ever Espino-Gonzalez and Danial Ahwazi and Jordana Freemantle and Amy Ehrlich and Charline Jomard and Jonas Brorson and Agnete Schou and Jean Farup and Julien Gondin and Jesper Just and Marc Foretz and Jonas Treebak and Marianne Agerholm and Kei Sakamoto},
journal = {Molecular metabolism},
year = {2026},
month = nov,
doi = {10.1016/j.molmet.2025.102294},
url = {https://hal.science/hal-05398089v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle
AU - Dipsikha Biswas
AU - Ever Espino-Gonzalez
AU - Danial Ahwazi
AU - Jordana Freemantle
AU - Amy Ehrlich
AU - Charline Jomard
AU - Jonas Brorson
AU - Agnete Schou
AU - Jean Farup
AU - Julien Gondin
AU - Jesper Just
AU - Marc Foretz
AU - Jonas Treebak
AU - Marianne Agerholm
AU - Kei Sakamoto
PY - 2026
DA - 2026/11/03
JO - Molecular metabolism
DO - 10.1016/j.molmet.2025.102294
UR - https://hal.science/hal-05398089v1
AB - Objective Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle. Methods Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1 -/- /γ3 -/- ) and single knockout (imγ1⁻ / ⁻ and imγ3⁻ / ⁻) mice were generated . Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed. Results snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo , glucose uptake stimulated by either AICAR or MK-8722 was abolished in imγ1⁻ / ⁻/γ3⁻ / ⁻ muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo . AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3⁻ / ⁻, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1⁻ / ⁻ mice. Conclusions While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
SN - 2212-8778
ER -