| Title | Fine-Tuning of PGC1 alpha Expression Regulates Cardiac Function and Longevity |
| Authors | Zhu, Xudong Shen, Weiyan Yao, Ke Wang, Hu Liu, Bo Li, Tangliang Song, Lijuan Diao, Daojun Mao, Genxiang Huang, Ping Li, Chengtao Zhang, Hongbo Zou, Yejun Qiu, Yugang Zhao, Yuzheng Wang, Wengong Yang, Yi Hu, Zeping Auwerx, Johan Loscalzo, Joseph Zhou, Yong Ju, Zhenyu |
| Affiliation | Hangzhou Normal Univ, Inst Aging Res, Sch Med, Hangzhou, Zhejiang, Peoples R China Jinan Univ, Inst Aging & Regenerat Med, Guangzhou Regenerat Med & Hlth Guangdong Lab, Key Lab Regenerat Med,Minist Educ, Jinan, Shandong, Peoples R China Tsinghua Univ, Sch Pharmaceut Sci, Beijing, Peoples R China Gannan Med Univ, Affiliated Hosp 1, Dept Cardiol, Ganzhou, Peoples R China Zhejiang Hosp, Geriatr Res Inst Zhejiang Prov, Zhejiang Prov Key Lab Geriatr, Dept Geriatr, Hangzhou, Zhejiang, Peoples R China Minist Justice, Shanghai Forens Serv Platform, Shanghai Key Lab Forens Med, Inst Forens Sci, Shanghai, Peoples R China Ecole Polytech Fed Lausanne, Inst Bioengn, Lab Integrat & Syst Physiol, Lausanne, Switzerland East China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg Technol, State Key Lab Bioreactor Engn, Synthet Biol & Biotechnol Lab, Shanghai, Peoples R China Weifang Med Univ, Sch Rehabil Med, Weifang, Peoples R China Peking Univ, Sch Basic Med Sci, Beijing Key Lab Prot Posttranslat Modificat & Cel, Hlth Sci Ctr,Dept Biochem & Mol Biol, Beijing, Peoples R China Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA Capital Med Univ, Beijing Sanbo Brain Hosp, Beijing, Peoples R China |
| Keywords | aging autophagy heart mitochondria telomerase |
| Issue Date | 2019 |
| Publisher | CIRCULATION RESEARCH |
| Abstract | Rationale: PGC1 alpha (peroxisome proliferator-activated receptor gamma coactivator 1 alpha) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1 alpha expression as a therapy, for instance, causing cardiomyopathy. Objective: To determine whether a fine-tuning of PGC1 alpha expression is essential for cardiac homeostasis in a context-dependent manner. Methods and Results: Moderate cardiac-specific PGC1 alpha overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc(-/-) (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1 alpha expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1 alpha expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1 alpha (PGC1 alpha(OE)) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1 alpha knock in in G3 (G3 PGC1 alpha(OE)) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1 alpha(OE) mice. In the context of telomere dysfunction, PGC1 alpha induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. Conclusions: Fine-tuning the expression of PGC1 alpha is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1 alpha-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies. |
| URI | http://hdl.handle.net/20.500.11897/545164 |
| ISSN | 0009-7330 |
| DOI | 10.1161/CIRCRESAHA.119.315529 |
| Indexed | SCI(E) |
| Appears in Collections: | 基础医学院 |
