, Volume 57, Issue 6, pp 1232–1241

Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice

  • Hui-Young Lee
  • Arijeet K. Gattu
  • João-Paulo G. Camporez
  • Shoichi Kanda
  • Blas Guigni
  • Mario Kahn
  • Dongyan Zhang
  • Thomas Galbo
  • Andreas L. Birkenfeld
  • Francois R. Jornayvaz
  • Michael J. Jurczak
  • Cheol Soo Choi
  • Zhen Yan
  • R. Sanders Williams
  • Gerald I. Shulman
  • Varman T. Samuel



Aerobic exercise increases muscle glucose and improves insulin action through numerous pathways, including activation of Ca2+/calmodulin-dependent protein kinases (CAMKs) and peroxisome proliferator γ coactivator 1α (PGC-1α). While overexpression of PGC-1α increases muscle mitochondrial content and oxidative type I fibres, it does not improve insulin action. Activation of CAMK4 also increases the content of type I muscle fibres, PGC-1α level and mitochondrial content. However, it remains unknown whether CAMK4 activation improves insulin action on glucose metabolism in vivo.


The effects of CAMK4 activation on skeletal muscle insulin action were quantified using transgenic mice with a truncated and constitutively active form of CAMK4 (CAMK4) in skeletal muscle. Tissue-specific insulin sensitivity was assessed in vivo using a hyperinsulinaemic–euglycaemic clamp and isotopic measurements of glucose metabolism.


The rate of insulin-stimulated whole-body glucose uptake was increased by ∼25% in CAMK4 mice. This was largely attributed to an increase of ∼60% in insulin-stimulated glucose uptake in the quadriceps, the largest hindlimb muscle. These changes were associated with improvements in insulin signalling, as reflected by increased phosphorylation of Akt and its substrates and an increase in the level of GLUT4 protein. In addition, there were extramuscular effects: CAMK4 mice had improved hepatic and adipose insulin action. These pleiotropic effects were associated with increased levels of PGC-1α-related myokines in CAMK4 skeletal muscle.


Activation of CAMK4 enhances mitochondrial biogenesis in skeletal muscle while also coordinating improvements in whole-body insulin-mediated glucose.


Hyperinsulinaemic–euglycaemic clamp Muscle insulin resistance Myokines 



AMP-activated protein kinase


160 kDa substrate of the Akt serine/threonine kinase


Ca2+/calmodulin-dependent protein kinase


Truncated and constitutively active form of CAMK


cAMP response element binding protein




Endogenous glucose production


Extensor digitorum longus


Histone deacetylase 5


Myocyte enhancer factor 2


National Institutes of Health


Novel protein kinase C


Peroxisome proliferator-activated receptor γ coactivator 1α


Protein phosphatase type 2A


Protein phosphatase type 2A catalytic subunit


Akt1 substrate 1 (proline-rich)


Uncoupling protein 1 (mitochondrial, proton carrier)


Voltage-dependent ion channel


White adipose tissue


White quadriceps

Supplementary material

125_2014_3212_MOESM1_ESM.pdf (63 kb)
ESM Table 1(PDF 62 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014

Authors and Affiliations

  • Hui-Young Lee
    • 1
    • 2
    • 3
  • Arijeet K. Gattu
    • 1
    • 4
  • João-Paulo G. Camporez
    • 1
  • Shoichi Kanda
    • 1
  • Blas Guigni
    • 1
  • Mario Kahn
    • 1
  • Dongyan Zhang
    • 1
  • Thomas Galbo
    • 1
  • Andreas L. Birkenfeld
    • 1
    • 5
  • Francois R. Jornayvaz
    • 1
  • Michael J. Jurczak
    • 1
  • Cheol Soo Choi
    • 1
    • 3
  • Zhen Yan
    • 6
  • R. Sanders Williams
    • 7
  • Gerald I. Shulman
    • 1
    • 2
    • 8
  • Varman T. Samuel
    • 1
    • 4
  1. 1.Department of Internal MedicineYale University School of MedicineNew HavenUSA
  2. 2.Howard Hughes Medical InstituteYale University School of MedicineNew HavenUSA
  3. 3.Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheonSouth Korea
  4. 4.Veteran’s Affairs Medical CenterWest HavenUSA
  5. 5.Department of EndocrinologyCharité – University School of MedicineBerlinGermany
  6. 6.Department of MedicineUniversity of VirginiaCharlottesvilleUSA
  7. 7.J. David Gladstone InstitutesSan FranciscoUSA
  8. 8.Department of Cellular & Molecular PhysiologyYale University School of MedicineNew HavenUSA

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