Normal hypertrophy accompanied by phosphoryation and activation of AMP-activated protein kinase α1 following overload in LKB1 knockout mice

Sean L. Mcgee, Kirsty J. Mustard, D. Grahame Hardie, Keith Baar

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The activation of the AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin complex 1 (mTORC1) is hypothesized to underlie the fact that muscle growth following resistance exercise is decreased by concurrent endurance exercise. To directly test this hypothesis, the capacity for muscle growth was determined in mice lacking the primary upstream kinase for AMPK in skeletal muscle, LKB1. Following either 1 or 4 weeks of overload, there was no difference in muscle growth between the wild type (wt) and LKB1-/- mice (1 week: wt, 38.8 ± 7.75%; LKB1-/-, 27.8 ± 12.98%; 4 week: wt, 75.8 ± 15.2%; LKB1-/-, 85.0 ± 22.6%). In spite of the fact that the LKB1 had been knocked out in skeletal muscle, the phosphorylation and activity of the α1 isoform of AMPK were markedly increased in both the wt and the LKB1-/- mice. To identify the upstream kinase(s) responsible, we studied potential upstream kinases other than LKB1. The activity of both Ca2+-calmodulin-dependent protein kinase kinase α(CaMKKα)(5.05 ± 0.86-fold) and CaMKKβ (10.1 ± 2.59-fold) increased in the overloaded muscles, and this correlated with their increased expression. Phosphorylation of TAK-1 also increased 10-fold following overload in both the wt and LKB1 mice. Even though the α1 isoform of AMPK was activated by overload, there were no increases in expression of mitochondrial proteins or GLUT4, indicating that the α1 isoform is not involved in these metabolic adaptations. The phosphorylation of TSC2, an upstream regulator of the TORC1 pathway, at the AMPK site (Ser1345) was increased in response to overload, and this was not affected by LKB1 deficiency. Taken together, these data suggest that the α1 isoform of AMPK is preferentially activated in skeletal muscle following overload in the absence of metabolic adaptations, suggesting that this isoform might be important in the regulation of growth but not metabolism.

Original languageEnglish (US)
Pages (from-to)1731-1741
Number of pages11
JournalJournal of Physiology
Volume586
Issue number6
DOIs
StatePublished - Mar 15 2008
Externally publishedYes

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AMP-Activated Protein Kinases
Knockout Mice
Hypertrophy
Protein Isoforms
Phosphotransferases
Muscles
Calcium-Calmodulin-Dependent Protein Kinases
Skeletal Muscle
Phosphorylation
Growth
Mitochondrial Proteins

ASJC Scopus subject areas

  • Physiology

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Normal hypertrophy accompanied by phosphoryation and activation of AMP-activated protein kinase α1 following overload in LKB1 knockout mice. / Mcgee, Sean L.; Mustard, Kirsty J.; Hardie, D. Grahame; Baar, Keith.

In: Journal of Physiology, Vol. 586, No. 6, 15.03.2008, p. 1731-1741.

Research output: Contribution to journalArticle

Mcgee, Sean L. ; Mustard, Kirsty J. ; Hardie, D. Grahame ; Baar, Keith. / Normal hypertrophy accompanied by phosphoryation and activation of AMP-activated protein kinase α1 following overload in LKB1 knockout mice. In: Journal of Physiology. 2008 ; Vol. 586, No. 6. pp. 1731-1741.
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abstract = "The activation of the AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin complex 1 (mTORC1) is hypothesized to underlie the fact that muscle growth following resistance exercise is decreased by concurrent endurance exercise. To directly test this hypothesis, the capacity for muscle growth was determined in mice lacking the primary upstream kinase for AMPK in skeletal muscle, LKB1. Following either 1 or 4 weeks of overload, there was no difference in muscle growth between the wild type (wt) and LKB1-/- mice (1 week: wt, 38.8 ± 7.75{\%}; LKB1-/-, 27.8 ± 12.98{\%}; 4 week: wt, 75.8 ± 15.2{\%}; LKB1-/-, 85.0 ± 22.6{\%}). In spite of the fact that the LKB1 had been knocked out in skeletal muscle, the phosphorylation and activity of the α1 isoform of AMPK were markedly increased in both the wt and the LKB1-/- mice. To identify the upstream kinase(s) responsible, we studied potential upstream kinases other than LKB1. The activity of both Ca2+-calmodulin-dependent protein kinase kinase α(CaMKKα)(5.05 ± 0.86-fold) and CaMKKβ (10.1 ± 2.59-fold) increased in the overloaded muscles, and this correlated with their increased expression. Phosphorylation of TAK-1 also increased 10-fold following overload in both the wt and LKB1 mice. Even though the α1 isoform of AMPK was activated by overload, there were no increases in expression of mitochondrial proteins or GLUT4, indicating that the α1 isoform is not involved in these metabolic adaptations. The phosphorylation of TSC2, an upstream regulator of the TORC1 pathway, at the AMPK site (Ser1345) was increased in response to overload, and this was not affected by LKB1 deficiency. Taken together, these data suggest that the α1 isoform of AMPK is preferentially activated in skeletal muscle following overload in the absence of metabolic adaptations, suggesting that this isoform might be important in the regulation of growth but not metabolism.",
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