Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart

  • Wenjun Yan
  • Haifeng Zhang
  • Peilin Liu
  • Han Wang
  • Jingyi Liu
  • Chao Gao
  • Yi Liu
  • Kun Lian
  • Lu Yang
  • Lu Sun
  • Yunping Guo
  • Lijian Zhang
  • Ling Dong
  • Wayne Bond Lau
  • Erhe Gao
  • Feng Gao
  • Lize Xiong
  • Haichang Wang
  • Yan QuEmail author
  • Ling TaoEmail author
Original Contribution


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.


Adiponectin Mitochondrial biogenesis dysfunction AMPK PGC-1α Diabetes Myocardial ischemia 



The work presented here was carried out in collaboration between all authors. Ling Tao and Yan Qu defined the research theme and revised the manuscript critically. Wenjun Yan, Haifeng Zhang and Peilin Liu designed methods and experiments, carried out the laboratory experiments, and wrote the paper. Han Wang, Jingyi Liu, Chao Gao, Yi Liu, Kun Lian, Lu Yang, Lu Sun, Yunping Guo, Lijian Zhang, Ling Dong, Wayne Bond Lau, Erhe Gao, Feng Gao, Lize Xiong and Haichang Wang collected and analyzed the data, interpreted the results. The authors thank Chen Keke and Li Youyou, Department of physiology, Fourth Military Medical University, for technical support in cell culture and western blot. This work was supported by the National Science Fund for Distinguished Young Scholars (No. 81225001), National Program on Key Basic Research Project (973 Program, No. 2013CB531200), National Natural Science Foundation of China (Nos. 81170186, 81070676, 81070951, 81100136, 81270330), National 863 Project of China (No. 2009AA02Z104), and the Subject Boosting Project of Xijing Hospital (No. XJZT08Z02).

Conflict of interest

The authors declare that no conflict of interest exists.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Wenjun Yan
    • 1
  • Haifeng Zhang
    • 4
  • Peilin Liu
    • 1
  • Han Wang
    • 1
  • Jingyi Liu
    • 1
  • Chao Gao
    • 1
  • Yi Liu
    • 1
  • Kun Lian
    • 1
  • Lu Yang
    • 1
  • Lu Sun
    • 1
  • Yunping Guo
    • 1
  • Lijian Zhang
    • 1
  • Ling Dong
    • 5
  • Wayne Bond Lau
    • 6
  • Erhe Gao
    • 6
  • Feng Gao
    • 5
  • Lize Xiong
    • 3
  • Haichang Wang
    • 1
  • Yan Qu
    • 2
    Email author
  • Ling Tao
    • 1
    Email author
  1. 1.Department of CardiologyXijing Hospital, The Fourth Military Medical UniversityXianChina
  2. 2.Department of NeurosurgeryXijing Hospital, The Fourth Military Medical UniversityXianChina
  3. 3.Department of AnesthesiologyXijing Hospital, The Fourth Military Medical UniversityXianChina
  4. 4.Center of Teaching ExperimentXijing Hospital, The Fourth Military Medical UniversityXianChina
  5. 5.Department of PhysiologyThe Fourth Military Medical UniversityXianChina
  6. 6.Department of Emergency Medicine, Center of Translational MedicineThomas Jefferson UniversityPhiladelphiaUSA

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