The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport.
The small molecule kinase inhibitor SBI-0206965 was originally described as a specific inhibitor of ULK1/2. More recently, it was reported to effectively inhibit AMPK and several studies now report its use as an AMPK inhibitor. Currently, we investigated the specificity of SBI-0206965 in incubated mouse skeletal muscle, measuring the effect on analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated AMPK-dependent glucose transport and insulin-stimulated AMPK-independent glucose uptake. Pre-treatment with 10 µM SBI-0206965 for 50 min potently suppressed AICAR-stimulated glucose transport in both the extensor digitorum longus (EDL) and soleus muscle. This was despite only a modest lowering of AICAR-stimulated AMPK activation measured as ACC2 Ser212, while ULK1/2 Ser555 phosphorylation was prevented. Insulin-stimulated glucose transport was also potently inhibited by SBI-0206965 in soleus. No major changes were observed on insulin-stimulated cell signaling. No general effect of SBI-0206965 on intracellular membrane morphology was observed by transmission electron microscopy. As insulin is known to neither activate AMPK nor require AMPK to stimulate glucose transport, and insulin inhibits ULK1/2 activity, these data strongly suggest that SBI-0206965 has a non-specific off-target inhibitory effect on muscle glucose transport. Thus, SBI-0206965 is not a specific inhibitor of the AMPK/ULK-signaling axis in skeletal muscle, and data generated with this inhibitor must be interpreted with caution.
['Knudsen|Jonas R|JR|0000-0002-5471-491X', 'Madsen|Agnete B|AB|', 'Persson|Kaspar W|KW|', 'Henríquez-Olguín|Carlos|C|', 'Li|Zhencheng|Z|', 'Jensen|Thomas E|TE|0000-0001-6139-8268']
D055372:AMP-Activated Protein Kinases D000620:Aminoimidazole Carboxamide D000818:Animals D000071189:Autophagy-Related Protein-1 Homolog D001549:Benzamides D001692:Biological Transport D005260:Female D005947:Glucose D007004:Hypoglycemic Agents D007328:Insulin D051379:Mice D008810:Mice, Inbred C57BL D018482:Muscle, Skeletal D011743:Pyrimidines D012265:Ribonucleotides
ULK1/2 AMPK SBI-0206965 kinase inhibitor skeletal muscle