| Title: |
Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle |
| Authors: |
Biswas, Dipsikha; Espino-Gonzalez, Ever; Ahwazi, Danial; Freemantle, Jordana B; Ehrlich, Amy M; Jomard, Charline; Brorson, Jonas; Schou, Agnete N; Farup, Jean; Gondin, Julien; Just, Jesper; Foretz, Marc; Treebak, Jonas T; Agerholm, Marianne; Sakamoto, Kei |
| Source: |
Biswas, D, Espino-Gonzalez, E, Ahwazi, D, Freemantle, J B, Ehrlich, A M, Jomard, C, Brorson, J, Schou, A N, Farup, J, Gondin, J, Just, J, Foretz, M, Treebak, J T, Agerholm, M & Sakamoto, K 2026, 'Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle', Molecular Metabolism, vol. 103, 102294. https://doi.org/10.1016/j.molmet.2025.102294 |
| Publication Year: |
2026 |
| Collection: |
Aarhus University: Research |
| Subject Terms: |
AICAR; AMP-activated protein kinase; Glucose uptake; MK-8722; Single nucleus RNA sequencing |
| Description: |
Objectives: 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 severely blunted 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2212-8778 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41325841; info:eu-repo/semantics/altIdentifier/pissn/2212-8778 |
| DOI: |
10.1016/j.molmet.2025.102294 |
| Availability: |
https://pure.au.dk/portal/en/publications/b2253bf4-ee55-436f-9b27-3817b26c5b54; https://doi.org/10.1016/j.molmet.2025.102294; https://www.scopus.com/pages/publications/105024318645 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.161E4136 |
| Database: |
BASE |