AIMS/HYPOTHESIS
Increased extracellular matrix (ECM) collagen is a characteristic of muscle insulin resistance. MMP9 is a primary enzyme that degrades collagen IV (ColIV). As a component of the basement membrane, ColIV plays a key role in ECM remodeling. The hypotheses that genetic deletion of MMP9 in mice 1) increases muscle ColIV, 2) induces insulin resistance in lean mice, and 3) worsens diet-induced muscle insulin resistance were tested.
METHODS
Wild type (mmp9+/+) and MMP9 null (mmp9−/−) mice were chow or high fat (HF) fed for 16wks. Insulin action was measured by the hyperinsulinemic, euglycemic clamp in conscious weight-matched surgically catheterized mice.
RESULTS
mmp9−/− and HF feeding independently increased muscle ColIV. ColIV in HF-fed mmp9−/− was further increased. mmp9−/− did not affect fasting insulin or glucose in chow- or HF-fed mice. 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−/−. In contrast, HF-fed mmp9−/− decreased GIR, insulin-stimulated increase in Rd, and muscle Rg. Insulin-stimulated suppression of EndoRa was however, remained the same between HF-fed mmp9−/− and mmp9+/+. Decreased muscle Rg in HF-fed mmp9−/− was associated with decreased muscle capillaries.
CONCLUSION/INTERPRETATION
Despite increased muscle ColIV, genetic deletion of MMP9 does not induce insulin resistance in lean mice. In contrast, it results in a more profound insulin resistant state, specifically in skeletal muscle in HF-fed mice. These results highlight the importance of ECM remodeling in determining muscle insulin resistance in the presence of HF diet.