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

Kang L, Mayes WH, James FD, Bracy DP, Wasserman DH
Diabetologia. 2014 57 (3): 603-13

PMID: 24305966 · PMCID: PMC4155606 · DOI:10.1007/s00125-013-3128-1

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.

MeSH Terms (15)

Animals Blood Glucose Body Weight Collagen Type V Diet, High-Fat Extracellular Matrix Gene Deletion Glucose Clamp Technique Immunohistochemistry Insulin Insulin Resistance Matrix Metalloproteinase 9 Mice Muscle, Skeletal Vascular Endothelial Growth Factor A

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