Fine-Tuning of PGC1α Expression Regulates Cardiac Function and Longevity.

Zhu X; Shen W; Yao K; Wang H; Liu B; Li T; Song L; Diao D; Mao G; Huang P; Li C; Zhang H; Zou Y; Qiu Y; Zhao Y; Wang W; Yang Y; Hu Z; Auwerx J; Loscalzo J; Zhou Y; Ju Z

doi:10.1161/CIRCRESAHA.119.315529

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Journal article

Fine-Tuning of PGC1α Expression Regulates Cardiac Function and Longevity.

Zhu X From the Institute of Aging Research, Hangzhou Normal University School of Medicine, China (X.Z., H.W., T.L.).
Shen W Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, China (W.S., H.W., B.L., D.D., Z.J.).
Yao K School of Pharmaceutical Sciences, Tsinghua University, Beijing, China (K.Y., Z.H.).
Wang H From the Institute of Aging Research, Hangzhou Normal University School of Medicine, China (X.Z., H.W., T.L.).
Liu B Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, China (W.S., H.W., B.L., D.D., Z.J.).
Li T From the Institute of Aging Research, Hangzhou Normal University School of Medicine, China (X.Z., H.W., T.L.).
Song L Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (L.S.).
Diao D Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, China (W.S., H.W., B.L., D.D., Z.J.).
Mao G Department of Geriatrics, Zhejiang Provincial Key Lab of Geriatrics, Geriatrics Research Institute of Zhejiang Province, Zhejiang Hospital, Hangzhou, China (G.M.).
Huang P Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Sciences, Ministry of Justice, China (P.H., C.L.).
Li C Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Sciences, Ministry of Justice, China (P.H., C.L.).
Zhang H Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Federale de Lausanne, Switzerland (H.Z., J.A.).
Zou Y Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology (Y. Zou, Y. Zhao, Y.Y.).
Qiu Y School of Rehabilitation Medicine, Weifang Medical University, China (Y.Q.).
Zhao Y Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology (Y. Zou, Y. Zhao, Y.Y.).
Wang W Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, China (W.W.).
Yang Y Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology (Y. Zou, Y. Zhao, Y.Y.).
Hu Z School of Pharmaceutical Sciences, Tsinghua University, Beijing, China (K.Y., Z.H.).
Auwerx J Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Federale de Lausanne, Switzerland (H.Z., J.A.).
Loscalzo J Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.L.).
Zhou Y Beijing Sanbo Brain Hospital, Capital Medical University, China (Y. Zhou).
Ju Z Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, China (W.S., H.W., B.L., D.D., Z.J.).

2019-08-16

Published in:

Circulation research. - 2019

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

English RATIONALE
PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy.

OBJECTIVE
To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner.

METHODS AND RESULTS
Moderate cardiac-specific PGC1α 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 PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) 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 PGC1α knock in in G3 (G3 PGC1αOE) 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 PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart.

CONCLUSIONS
Fine-tuning the expression of PGC1α 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 PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.

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