Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice.
Obesity and type 2 diabetes are major risk factors for peripheral arterial disease in humans, which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO).



DIO mice (n = 7) underwent unilateral femoral artery ligation and recovered for 2 wks followed by 4 wks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia (SI) group (n = 7) had femoral artery ligation without exercise. The contralateral limb muscles of SI served as control. Muscles were examined for capillary density, myofiber cross-sectional area, cytokine levels, and phosphorylation of STAT3 and ERK1/2.



Exercise significantly enhanced capillary density (P < 0.01) and markedly lowered cross-sectional area (P < 0.001) in demand ischemia compared with SI. These findings coincided with a significant increase in granulocyte colony-stimulating factor (P < 0.001) and interleukin-7 (P < 0.01) levels. In addition, phosphorylation levels of STAT3 and ERK1/2 (P < 0.01) were increased, whereas UCP1 and monocyte chemoattractant protein-1 protein levels were lower (P < 0.05) without altering vascular endothelial growth factor and tumor necrosis factor alpha protein levels. Demand ischemia increased the PGC1α messenger RNA (P < 0.001) without augmenting PGC1α protein levels.



Exercise-induced limb demand ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in tumor necrosis factor alpha, lower vascular endothelial growth factor, and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO.
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: halbadawi@mgh.harvard.edu.
Hassan
H
Albadawi
Harvard Medical School, Boston, Massachusetts; Department of Surgery, Shriners Burns Institute, Massachusetts General Hospital, Boston, Massachusetts.
A Aria
AA
Tzika
Harvard Medical School, Boston, Massachusetts; Section on Vascular Cell Biology, Joslin Diabetes Center, Boston, Massachusetts.
Christian
C
Rask-Madsen
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
Lindsey M
LM
Crowley
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
Michael W
MW
Koulopoulos
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
Hyung-Jin
HJ
Yoo
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Michael T
MT
Watkins
D000222:Adaptation, Physiological; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D002196:Capillaries; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000378:metabolism
D042501:Angiogenic Proteins; D016207:Cytokines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1
Angiogenesis; Demand ischemia; Granulocyte colony stimulating factor; Myofiber atrophy; Obesity; Peripheral arterial disease