AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

Abstract

AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in wholebody AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.is an evolutionarily conserved stress-sensing kinase that controls energy metabolism and appetite by responding to nutrients and hormones (1). The regulation of AMPK activity depends on AMP and ADP regulated phosphorylation of the α catalytic subunit at T172 by the upstream kinases LKB1 and Ca 2+ /CaM-dependent protein kinase kinase (CaMKKβ; refs. 2 and 3). AMPK exists as a heterotrimer, consisting of an α catalytic subunit (α1, α2), a scaffolding β subunit (β1, β2) and a nucleotide-binding γ subunit (γ1, γ2, γ3) (1). The C-terminal of the β subunit contains a highly conserved α and γ subunit-binding sequence (SBS) that is required for the formation of a stable, active AMPK αβγ complex (4). We recently reported on the physiological effects of germline deletion of β1 (5) and β2 (6) isoforms in mice. We showed that β1 null mice have reduced AMPK α-subunit expression and activity in liver, adipose tissue and the hypothalamus (5). In contrast, AMPK β2 null mice have reduced AMPK activity in skeletal muscle, are aminoimidazole carboxamide ribonucleotide (AICAR) insensitive and have reduced exercise tolerance despite a greater than 50% increase in muscle β1 protein expression (6). The phenotype of β2 null mice was similar to that of mice lacking α2 (7) or γ3 (8) subunits or muscle-specific overexpression of an α2 kinase dead (KD) mutation (9, 10).During exercise, AMPK is activated in an intensity-dependent manner (for review, see ref. 11). Mice with reduced AMPK in muscle are exercise intolerant, an effect shown not to be due to cardiac impairments in AMPK (12-14). However, the cause for this reduction in exercise capacity remains largely unknown, because mitochondrial content and glucose uptake are not altered (6,7,10,12,(15)(16)(17) or onl...

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