Hassan Albadawi1, Rahmi Oklu2, John D Milner3, Thuy P Uong3, Hyung-Jin Yoo3, William G Austen4, Michael T Watkins3. 1. Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: halbadawi@mgh.harvard.edu. 2. Division of Vascular and Interventional Radiology, Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 3. Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 4. Division of Plastic and Reconstructive Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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.
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 diabeticmice subjected to demand or sedentary ischemia. MATERIALS AND METHODS:Unilateral hind limb demand ischemia was created in a group of diet-induced obesemice 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 obesemice, 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.
Authors: Iraklis I Pipinos; Stanley A Swanson; Zhen Zhu; Aikaterini A Nella; Dustin J Weiss; Tanuja L Gutti; Rodney D McComb; B Timothy Baxter; Thomas G Lynch; George P Casale Journal: Am J Physiol Regul Integr Comp Physiol Date: 2008-05-14 Impact factor: 3.619
Authors: Amy C Keller; Leslie A Knaub; Matthew W Miller; Nicholas Birdsey; Dwight J Klemm; Jane E B Reusch Journal: J Cardiovasc Pharmacol Date: 2015-02 Impact factor: 3.105
Authors: Dustin J Weiss; George P Casale; Panagiotis Koutakis; Aikaterini A Nella; Stanley A Swanson; Zhen Zhu; Dimitrios Miserlis; Jason M Johanning; Iraklis I Pipinos Journal: J Transl Med Date: 2013-09-25 Impact factor: 5.531
Authors: Hassan Albadawi; A Aria Tzika; Christian Rask-Madsen; Lindsey M Crowley; Michael W Koulopoulos; Hyung-Jin Yoo; Michael T Watkins Journal: J Surg Res Date: 2016-06-08 Impact factor: 2.192