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Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice

Diabetologia volume 57, pages 603–613 (2014)Cite this article

Abstract

Aims/hypothesis

Increased extracellular matrix (ECM) collagen is a characteristic of muscle insulin resistance. Matrix metalloproteinase (MMP) 9 is a primary enzyme that degrades collagen IV (ColIV). As a component of the basement membrane, ColIV plays a key role in ECM remodelling. We tested the hypotheses that genetic deletion of MMP9 in mice increases muscle ColIV, induces insulin resistance in lean mice and worsens diet-induced muscle insulin resistance.

Methods

Wild-type (Mmp9 +/+) and Mmp9-null (Mmp9 −/−) mice were chow or high-fat (HF) fed for 16 weeks. Insulin action was measured by the hyperinsulinaemic–euglycaemic clamp in conscious weight-matched surgically catheterised mice.

Results

Mmp9 −/− and HF feeding independently increased muscle ColIV. ColIV in HF-fed Mmp9 −/− mice was further increased. Mmp9 −/− did not affect fasting insulin or glucose in chow- or HF-fed mice. The glucose infusion rate (GIR), endogenous glucose appearance (EndoRa) and glucose disappearance (Rd) rates, and a muscle glucose metabolic index (Rg), were the same in chow-fed Mmp9 +/+ and Mmp9 −/− mice. In contrast, HF-fed Mmp9 −/− mice had decreased GIR, insulin-stimulated increase in Rd and muscle Rg. Insulin-stimulated suppression of EndoRa, however, remained the same in HF-fed Mmp9 −/− and Mmp9 +/+ mice. Decreased muscle Rg in HF-fed Mmp9 −/− was associated with decreased muscle capillaries.

Conclusions/interpretation

Despite increased muscle ColIV, genetic deletion of MMP9 does not induce insulin resistance in lean mice. In contrast, this deletion results in a more profound state of insulin resistance, specifically in the skeletal muscle of HF-fed mice. These results highlight the importance of ECM remodelling in determining muscle insulin resistance in the presence of HF diet.

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Abbreviations

[14C]2DG:

2-Deoxy[14C]glucose

ColIV:

Collagen IV

ECM:

Extracellular matrix

EndoRa:

Endogenous glucose appearance rate

GIR:

Glucose infusion rate

HF:

High-fat

ICv :

Hyperinsulinaemic–euglycaemic clamp

MMP:

Matrix metalloproteinase

Ra:

Glucose appearance rate

Rd:

Glucose disappearance rate

Rg:

Glucose metabolic index

SVL:

Superficial vastus lateralis

VEGF:

Vascular endothelial growth factor

vWF:

von Willebrand factor

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Acknowledgements

We would like to thank the Vanderbilt Translational Pathology Shared Resource for performing the immunohistochemical staining of ColIV, CD31 and vWF. Part of the data from this study has been orally presented at the American Diabetes Association 72nd Scientific Sessions in 2012 and an abstract was published in ‘Orals’, Diabetes, 2012.

Funding

This work was supported by National Institutes of Health Grants DK054902 (DHW) and DK059637 (Mouse Metabolic Phenotyping Center; DHW). We would also like to thank the Vanderbilt Diabetes Research and Training Center (DK020593).

Contribution statement

LK, was responsible for the experimental design and researched data, contributed to the discussion and wrote the manuscript. WHM, FDJ and DPB researched data and reviewed the manuscript. DHW was responsible for the experimental design, and reviewed data, contributed to the discussion and reviewed/edited the manuscript. All authors approved the final version of this manuscript.

Duality of interest

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

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University, 2215 Garland Ave, Nashville, TN, 37232, USA

    Li Kang, Wesley H. Mayes, Freyja D. James, Deanna P. Bracy & David H. Wasserman

  2. Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA

    Li Kang & David H. Wasserman

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  1. Li Kang
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  2. Wesley H. Mayes
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  3. Freyja D. James
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  5. David H. Wasserman
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Corresponding author

Correspondence to Li Kang.

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Kang, L., Mayes, W.H., James, F.D. et al. Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice. Diabetologia 57, 603–613 (2014). https://doi.org/10.1007/s00125-013-3128-1

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