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

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Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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

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Abbreviations

AMPK:

AMP-activated protein kinase

AS160:

160 kDa substrate of the Akt serine/threonine kinase

CAMK:

Ca2+/calmodulin-dependent protein kinase

CAMK4● :

Truncated and constitutively active form of CAMK

CREB:

cAMP response element binding protein

DAG:

Diacylglycerol

EGP:

Endogenous glucose production

EDL:

Extensor digitorum longus

HDAC5:

Histone deacetylase 5

MEF2:

Myocyte enhancer factor 2

NIH:

National Institutes of Health

nPKC:

Novel protein kinase C

PGC-1α:

Peroxisome proliferator-activated receptor γ coactivator 1α

PP2A:

Protein phosphatase type 2A

PP2A/C:

Protein phosphatase type 2A catalytic subunit

PRAS40:

Akt1 substrate 1 (proline-rich)

UCP1:

Uncoupling protein 1 (mitochondrial, proton carrier)

VDAC:

Voltage-dependent ion channel

WAT:

White adipose tissue

WQD:

White quadriceps

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Acknowledgements

The authors would like to thank D. W. Frederick, Y. Kosover, I. Moore and A. Groszmann (Yale University School of Medicine, New Haven, CT, USA) for expert technical assistance with the studies.

Funding

This work was supported by grants from the US Public Health Service (R01 DK-40936, P30 DK-45735, U24 DK-059635) and a VA Merit Award (VTS). ALB was supported by a grant from the German Research Foundation (DFG, BI1292/4-1). ZY was supported by NIH grant AR050429.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

HL, AKG, JGC, SK, BG, MK, DZ, TG, ALB, FRJ and MJJ performed experiments, analysed data and revised the manuscript; HL, CSC, ZY, RSW, GIS and VTS designed the study and revised the manuscript; HL, CSC, GIS, VTS were responsible for the conception of the study and drafting the article. All authors approved the final version. VTS is responsible for the integrity of the work as a whole.

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Authors and Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

    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, Gerald I. Shulman & Varman T. Samuel

  2. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

    Hui-Young Lee & Gerald I. Shulman

  3. Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, South Korea

    Hui-Young Lee & Cheol Soo Choi

  4. Veteran’s Affairs Medical Center, West Haven, CT, USA

    Arijeet K. Gattu & Varman T. Samuel

  5. Department of Endocrinology, Charité – University School of Medicine, Berlin, Germany

    Andreas L. Birkenfeld

  6. Department of Medicine, University of Virginia, Charlottesville, VA, USA

    Zhen Yan

  7. J. David Gladstone Institutes, San Francisco, CA, USA

    R. Sanders Williams

  8. Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    Gerald I. Shulman

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  1. Hui-Young Lee
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Corresponding author

Correspondence to Varman T. Samuel.

Additional information

Arijeet K. Gattu and João-Paulo G. Camporez contributed equally to this work.

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Lee, HY., Gattu, A.K., Camporez, JP.G. et al. Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia 57, 1232–1241 (2014). https://doi.org/10.1007/s00125-014-3212-1

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