| First Author | Bultot L | Year | 2016 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 311 |
| Issue | 4 | Pages | E706-E719 |
| PubMed ID | 27577855 | Mgi Jnum | J:241401 |
| Mgi Id | MGI:5901998 | Doi | 10.1152/ajpendo.00237.2016 |
| Citation | Bultot L, et al. (2016) Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle. Am J Physiol Endocrinol Metab 311(4):E706-E719 |
| abstractText | AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic alpha-subunit (alpha1 and alpha2) and regulatory beta (beta1 and beta2)- and gamma (gamma1, gamma2, gamma3)-subunits, which are uniquely distributed across different cell types. There has been keen interest in developing specific and isoform-selective AMPK-activating drugs for therapeutic use and also as research tools. Moreover, establishing ways of enhancing cellular AMPK activity would be beneficial for both purposes. Here, we investigated if a recently described potent AMPK activator called 991, in combination with the commonly used activator 5-aminoimidazole-4-carboxamide riboside or contraction, further enhances AMPK activity and glucose transport in mouse skeletal muscle ex vivo. Given that the gamma3-subunit is exclusively expressed in skeletal muscle and has been implicated in contraction-induced glucose transport, we measured the activity of AMPKgamma3 as well as ubiquitously expressed gamma1-containing complexes. We initially validated the specificity of the antibodies for the assessment of isoform-specific AMPK activity using AMPK-deficient mouse models. We observed that a low dose of 991 (5 muM) stimulated a modest or negligible activity of both gamma1- and gamma3-containing AMPK complexes. Strikingly, dual treatment with 991 and 5-aminoimidazole-4-carboxamide riboside or 991 and contraction profoundly enhanced AMPKgamma1/gamma3 complex activation and glucose transport compared with any of the single treatments. The study demonstrates the utility of a dual activator approach to achieve a greater activation of AMPK and downstream physiological responses in various cell types, including skeletal muscle. |
