title: Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart.
abstract: Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1α acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1α acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1α signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1α blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1α signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.
authors: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 147 West Changle Rd, Xian, 710032, China.
authors: Wenjun
authors: W
authors: Yan
authors: Haifeng
authors: H
authors: Zhang
authors: Peilin
authors: P
authors: Liu
authors: Han
authors: H
authors: Wang
authors: Jingyi
authors: J
authors: Liu
authors: Chao
authors: C
authors: Gao
authors: Yi
authors: Y
authors: Liu
authors: Kun
authors: K
authors: Lian
authors: Lu
authors: L
authors: Yang
authors: Lu
authors: L
authors: Sun
authors: Yunping
authors: Y
authors: Guo
authors: Lijian
authors: L
authors: Zhang
authors: Ling
authors: L
authors: Dong
authors: Wayne Bond
authors: WB
authors: Lau
authors: Erhe
authors: E
authors: Gao
authors: Feng
authors: F
authors: Gao
authors: Lize
authors: L
authors: Xiong
authors: Haichang
authors: H
authors: Wang
authors: Yan
authors: Y
authors: Qu
authors: Ling
authors: L
authors: Tao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D048909:Diabetes Complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D008933:Mitochondrial Swelling; D063269:Mitochondrial Turnover; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D045222:Electron Transport Chain Complex Proteins; D006609:High Mobility Group Proteins; D020738:Leptin; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases