AMP-activated protein kinase α2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle

To examine the role of AMP-activated protein kinase ( AMPK) in muscle glucose transport, we generated muscle-specific transgenic mice (TG) carrying cDNAs of inactive alpha 2 (alpha 2i TG) and alpha 1 (alpha 1i TG) catalytic subunits. Extensor digitorum longus (EDL) muscles from wild type and TG mice were isolated and subjected to a series of in vitro incubation experiments. In alpha 2i TG mice basal alpha 2 activity was barely detectable, whereas basal alpha 1 activity was only partially reduced. Known AMPK stimuli including 5-aminoimidazole-4-carboxamide-1- beta-4-ribofuranoside (AICAR), rotenone ( a Complex I inhibitor), dinitrophenol ( a mitochondrial uncoupler), muscle contraction, and sorbitol ( producing hyperosmolar shock) did not increase AMPK alpha 2 activity in alpha 2i TG mice, whereas alpha 1 activation was attenuated by only 30 - 50%. Glucose transport was measured in vitro using isolated EDL muscles from alpha 2i TG mice. AICAR- and rotenone-stimulated glucose transport was fully inhibited in alpha 2iTG mice; however, the lack of AMPK alpha 2 activity had no effect on contraction or sorbitol-induced glucose transport. Similar to these observations in vitro, contraction-stimulated glucose transport, assessed in vivo by 2-deoxy-D-[H-3] glucose incorporation into EDL, tibialis anterior, and gastrocnemius muscles, was normal in alpha 2i TG mice. Thus, AMPK alpha 2 activation is essential for some, but not all, insulin-independent glucose transport. Muscle contraction- and hyperosmolarity-induced glucose transport may be regulated by a redundant mechanism in which AMPK alpha 2 is one of multiple signaling pathways.