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Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart.
Basic Res Cardiol 2013; 108(3):329BR

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+Show Affiliations

Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 147 West Changle Rd, Xian, 710032, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23460046

Citation

Yan, Wenjun, et al. "Impaired Mitochondrial Biogenesis Due to Dysfunctional adiponectin-AMPK-PGC-1α Signaling Contributing to Increased Vulnerability in Diabetic Heart." Basic Research in Cardiology, vol. 108, no. 3, 2013, p. 329.
Yan W, Zhang H, Liu P, et al. Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol. 2013;108(3):329.
Yan, W., Zhang, H., Liu, P., Wang, H., Liu, J., Gao, C., ... Tao, L. (2013). Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Research in Cardiology, 108(3), p. 329. doi:10.1007/s00395-013-0329-1.
Yan W, et al. Impaired Mitochondrial Biogenesis Due to Dysfunctional adiponectin-AMPK-PGC-1α Signaling Contributing to Increased Vulnerability in Diabetic Heart. Basic Res Cardiol. 2013;108(3):329. PubMed PMID: 23460046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. AU - Yan,Wenjun, AU - Zhang,Haifeng, AU - Liu,Peilin, AU - Wang,Han, AU - Liu,Jingyi, AU - Gao,Chao, AU - Liu,Yi, AU - Lian,Kun, AU - Yang,Lu, AU - Sun,Lu, AU - Guo,Yunping, AU - Zhang,Lijian, AU - Dong,Ling, AU - Lau,Wayne Bond, AU - Gao,Erhe, AU - Gao,Feng, AU - Xiong,Lize, AU - Wang,Haichang, AU - Qu,Yan, AU - Tao,Ling, Y1 - 2013/03/05/ PY - 2012/08/11/received PY - 2013/01/09/accepted PY - 2013/01/03/revised PY - 2013/3/6/entrez PY - 2013/3/6/pubmed PY - 2013/8/21/medline SP - 329 EP - 329 JF - Basic research in cardiology JO - Basic Res. Cardiol. VL - 108 IS - 3 N2 - 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. SN - 1435-1803 UR - https://www.unboundmedicine.com/medline/citation/23460046/Impaired_mitochondrial_biogenesis_due_to_dysfunctional_adiponectin_AMPK_PGC_1α_signaling_contributing_to_increased_vulnerability_in_diabetic_heart_ L2 - https://dx.doi.org/10.1007/s00395-013-0329-1 DB - PRIME DP - Unbound Medicine ER -