title: Subacute limb ischemia induces skeletal muscle injury in genetically susceptible mice independent of vascular density.
abstract: OBJECTIVE
  The primary preclinical model of peripheral artery disease, which involves acute limb ischemia (ALI), can result in appreciable muscle injury that is attributed to the acuity of the ischemic injury. A less acute model of murine limb ischemia using ameroid constrictors (ACs) has been developed in an attempt to mimic the chronic nature of human disease. However, there is currently little understanding of how genetics influence muscle injury following subacute arterial occlusion in the mouse.
  
  
  METHODS
  We investigated the influence of mouse genetics on skeletal muscle tissue survival, blood flow, and vascular density by subjecting two different mouse strains, C57BL/6 (BL6) and BALB/c, to ALI or subacute limb ischemia using single (1AC) or double (2AC) AC placement on the femoral artery.
  
  
  RESULTS
  Similar to ALI, the 2AC model resulted in significant tissue necrosis and limb perfusion deficits in genetically susceptible BALB/c but not BL6 mice. In the 1AC model, no outward evidence of tissue necrosis was observed, and there were no differences in limb blood flow between BL6 and BALB/c. However, BALB/c mice displayed significantly greater muscle injury, as evidenced by increased inflammation and myofiber atrophy, despite having no differences in CD31(+) and SMA(+) vascular density and area. BALB/c mice also displayed significantly greater centralized myonuclei, indicating increased muscle regeneration.
  
  
  CONCLUSIONS
  The susceptibility of skeletal muscle to ischemia-induced injury is at least partly independent of muscle blood flow and vascular density, consistent with a muscle cell autonomous response that is genetically determined. Further development of preclinical models of peripheral artery disease that more accurately reflect the nature of the human disease may allow more accurate identification of genetic targets for therapeutic intervention.
authors.affiliation: Department of Physiology, East Carolina University, Brody Medical Center, Greenville, NC; Diabetes and Obesity Institute, East Carolina Heart Institute, Brody Medical Center, Greenville, NC. Electronic address: mcclungj@ecu.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McClung
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McCord
authors.affiliation: Division of General Surgery, Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: Kevin
authors.initials: K
authors.lastname: Southerland
authors.affiliation: Department of Physiology, East Carolina University, Brody Medical Center, Greenville, NC; Diabetes and Obesity Institute, East Carolina Heart Institute, Brody Medical Center, Greenville, NC.
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Schmidt
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Padgett
authors.affiliation: Department of Physiology, East Carolina University, Brody Medical Center, Greenville, NC; Diabetes and Obesity Institute, East Carolina Heart Institute, Brody Medical Center, Greenville, NC.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000601:surgery; D020022:Genetic Predisposition to Disease; D006614:Hindlimb; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D018919:Neovascularization, Physiologic; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012038:Regeneration; D012039:Regional Blood Flow; D013045:Species Specificity; D013997:Time Factors
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; D019408:Platelet Endothelial Cell Adhesion Molecule-1