Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

Hassan Albadawi, A. Aria Tzika, Christian Rask-Madsen, Lindsey M. Crowley, Michael W. Koulopoulos, Hyung Jin Yoo, Michael T. Watkins

Research output: Contribution to journalArticle

Abstract

Background 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). Materials and methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)49-58
Number of pages10
JournalJournal of Surgical Research
Volume205
Issue number1
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Obese Mice
Ischemia
Extremities
Diet
Muscles
Obesity
Interleukin-7
Femoral Artery
Vascular Endothelial Growth Factor A
Ligation
Proteins
Tumor Necrosis Factor-alpha
Phosphorylation
Chemokine CCL2
Peripheral Arterial Disease
Granulocyte Colony-Stimulating Factor
Type 2 Diabetes Mellitus
Atrophy
Lower Extremity
Skeletal Muscle

Keywords

  • Angiogenesis
  • Demand ischemia
  • Granulocyte colony stimulating factor
  • Myofiber atrophy
  • Obesity
  • Peripheral arterial disease

ASJC Scopus subject areas

  • Surgery

Cite this

Albadawi, H., Tzika, A. A., Rask-Madsen, C., Crowley, L. M., Koulopoulos, M. W., Yoo, H. J., & Watkins, M. T. (2016). Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice. Journal of Surgical Research, 205(1), 49-58. https://doi.org/10.1016/j.jss.2016.06.001

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice. / Albadawi, Hassan; Tzika, A. Aria; Rask-Madsen, Christian; Crowley, Lindsey M.; Koulopoulos, Michael W.; Yoo, Hyung Jin; Watkins, Michael T.

In: Journal of Surgical Research, Vol. 205, No. 1, 01.09.2016, p. 49-58.

Research output: Contribution to journalArticle

Albadawi, H, Tzika, AA, Rask-Madsen, C, Crowley, LM, Koulopoulos, MW, Yoo, HJ & Watkins, MT 2016, 'Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice', Journal of Surgical Research, vol. 205, no. 1, pp. 49-58. https://doi.org/10.1016/j.jss.2016.06.001
Albadawi, Hassan ; Tzika, A. Aria ; Rask-Madsen, Christian ; Crowley, Lindsey M. ; Koulopoulos, Michael W. ; Yoo, Hyung Jin ; Watkins, Michael T. / Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice. In: Journal of Surgical Research. 2016 ; Vol. 205, No. 1. pp. 49-58.
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abstract = "Background 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). Materials and methods 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. Results 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. Conclusions 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.",
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AU - Crowley, Lindsey M.

AU - Koulopoulos, Michael W.

AU - Yoo, Hyung Jin

AU - Watkins, Michael T.

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N2 - Background 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). Materials and methods 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. Results 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. Conclusions 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.

AB - Background 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). Materials and methods 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. Results 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. Conclusions 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.

KW - Angiogenesis

KW - Demand ischemia

KW - Granulocyte colony stimulating factor

KW - Myofiber atrophy

KW - Obesity

KW - Peripheral arterial disease

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