Effect of limb demand ischemia on autophagy and morphology in mice

Hassan Albadawi, Rahmi Oklu, John D. Milner, Thuy P. Uong, Hyung Jin Yoo, William G. Austen, Michael T. Watkins

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background Obesity is a major risk factor for diabetes and peripheral arterial disease, which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism, which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia. Materials and methods Unilateral hind limb demand ischemia was created in a group of diet-induced obese mice after femoral artery ligation and 4 wk of daily exercise. A parallel group of mice underwent femoral artery ligation but remained sedentary for 4 wk. Hind limb muscles were analyzed for markers of autophagy, mitochondrial biogenesis, adenosine triphosphate, and muscle tissue morphology. Results At the end of the 4-wk exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator, LC3B-II/I ratio, or markers of mitochondrial biogenesis, optic atrophy/dynamin-related protein. In contrast, exercise significantly increased the level of mitochondrial protein-succinate dehydrogenase subunit-A and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle adenosine triphosphate or pS473-Akt levels. Conclusions Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice, but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with peripheral arterial disease are warranted.

Original languageEnglish (US)
Pages (from-to)515-524
Number of pages10
JournalJournal of Surgical Research
Volume198
Issue number2
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

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Keywords

  • Autophagy
  • Diet-induced obesity
  • Limb demand ischemia
  • Mitochondrial biogenesis
  • Muscle regeneration
  • Peripheral arterial disease
  • Type-2 diabetes

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)

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