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

Hayley M O'Neill, Stine J Maarbjerg, Justin D Crane, Jacob Jeppesen, Sebastian B Jørgensen, Jonathan D Schertzer, Olga Shyroka, Bente Kiens, Bryce J van Denderen, Mark A Tarnopolsky, Bruce E Kemp, Erik A Richter, Gregory R Steinberg

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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 whole-body 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.

Original languageEnglish
Pages (from-to)16092-7
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number38
DOIs
Publication statusPublished - 20 Sep 2011
Externally publishedYes

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AMP-Activated Protein Kinases
Glucose
Muscles
Skeletal Muscle
Mitochondria
Sequence Deletion
Protein Subunits
Running
Insulin Resistance
Protein Isoforms
Up-Regulation
Insulin
Diet
Enzymes

Cite this

O'Neill, Hayley M ; Maarbjerg, Stine J ; Crane, Justin D ; Jeppesen, Jacob ; Jørgensen, Sebastian B ; Schertzer, Jonathan D ; Shyroka, Olga ; Kiens, Bente ; van Denderen, Bryce J ; Tarnopolsky, Mark A ; Kemp, Bruce E ; Richter, Erik A ; Steinberg, Gregory R. / AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 38. pp. 16092-7.
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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 whole-body 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.",
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O'Neill, HM, Maarbjerg, SJ, Crane, JD, Jeppesen, J, Jørgensen, SB, Schertzer, JD, Shyroka, O, Kiens, B, van Denderen, BJ, Tarnopolsky, MA, Kemp, BE, Richter, EA & Steinberg, GR 2011, 'AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise' Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 38, pp. 16092-7. https://doi.org/10.1073/pnas.1105062108

AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. / O'Neill, Hayley M; Maarbjerg, Stine J; Crane, Justin D; Jeppesen, Jacob; Jørgensen, Sebastian B; Schertzer, Jonathan D; Shyroka, Olga; Kiens, Bente; van Denderen, Bryce J; Tarnopolsky, Mark A; Kemp, Bruce E; Richter, Erik A; Steinberg, Gregory R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 38, 20.09.2011, p. 16092-7.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AU - O'Neill, Hayley M

AU - Maarbjerg, Stine J

AU - Crane, Justin D

AU - Jeppesen, Jacob

AU - Jørgensen, Sebastian B

AU - Schertzer, Jonathan D

AU - Shyroka, Olga

AU - Kiens, Bente

AU - van Denderen, Bryce J

AU - Tarnopolsky, Mark A

AU - Kemp, Bruce E

AU - Richter, Erik A

AU - Steinberg, Gregory R

PY - 2011/9/20

Y1 - 2011/9/20

N2 - 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 whole-body 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.

AB - 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 whole-body 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.

U2 - 10.1073/pnas.1105062108

DO - 10.1073/pnas.1105062108

M3 - Article

VL - 108

SP - 16092

EP - 16097

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -