title: Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (-)-epigallocatechin-3-gallate.
abstract: Oxidative stress and mitochondrial dysfunction are known to play important roles in type 2 diabetes mellitus (T2DM) and insulin resistance. However, the pathology of T2DM remains complicated; in particular, the mechanisms of mitochondrial dysfunction in skeletal muscle and other insulin-sensitive tissues are as yet unclear. In the present study, we investigated the underlying mechanisms of oxidative stress and mitochondrial dysfunction by focusing on mitochondrial dynamics, including mitochondrial biogenesis and autophagy, in skeletal muscle of a nonobese diabetic animal model--the Goto-Kakizaki (GK) rat. The results showed that GK rats exhibited impaired glucose metabolism, increased oxidative stress and decreased mitochondrial function. These dysfunctions were found to be associated with induction of LC3B, Beclin1 and DRP1 (key molecules mediating the autophagy pathway), while they appeared not to affect the mitochondrial biogenesis pathway. In addition, (-)-epigallocatechin-3-gallate (EGCG) was tested as a potential autophagy-targeting nutrient, and we found that EGCG treatment improved glucose tolerance and glucose homeostasis in GK rats, and reduced oxidative stress and mitochondrial dysfunction in skeletal muscle. Amelioration of excessive muscle autophagy in GK rats through the down-regulation of the ROS-ERK/JNK-p53 pathway leads to improvement of glucose metabolism, reduction of oxidative stress and inhibition of mitochondrial loss and dysfunction. These results suggest (a) that hyperglycemia-associated oxidative stress may induce autophagy through up-regulation of the ROS-ERK/JNK-p53 pathway, which may contribute to mitochondrial loss in soleus muscle of diabetic GK rats, and (b) that EGCG may be a potential autophagy regulator useful in treatment of insulin resistance.
authors.affiliation: Department of Biology and Engineering, Institute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University School of Life Science and Technology, Xi'an 710049, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Weili
authors.initials: W
authors.lastname: Shen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Karin
authors.initials: K
authors.lastname: Wertz
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001786:Blood Glucose; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation; D005215:Fasting; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D016159:Tumor Suppressor Protein p53; D002392:Catechin; C045651:epigallocatechin gallate; D020928:Mitogen-Activated Protein Kinases