title: Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, 2215 Garland Ave, Nashville, TN, 37232, USA, li.kang@vanderbilt.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Mayes
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D024062:Collagen Type V / Q000378:metabolism*; D059305:Diet, High-Fat; D005109:Extracellular Matrix / Q000378:metabolism*; D017353:Gene Deletion; D015309:Glucose Clamp Technique; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D024062:Collagen Type V; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020780:Matrix Metalloproteinase 9