Related Experiment Video
Updated: Apr 25, 2026
Analyzing Oxygen Consumption Rate in Primary Cultured Mouse Neonatal Cardiomyocytes Using an Extracellular Flux Analyzer
Published on: February 13, 2019
Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts
Georgios Karamanlidis1, Lorena Garcia-Menendez1, Stephen C Kolwicz1
1Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
Abstract:
Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.
Insights
Moderate overexpression of peroxisome proliferator-activated receptor-γ coactivator alpha (PGC)-1α in the heart compromises survival and does not improve cardiac function during pressure overload, suggesting it is not a suitable therapeutic target for heart failure.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Molecular Medicine
Background:
- Mitochondrial dysfunction is linked to heart failure.
- The peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway is downregulated in heart failure models.
Purpose of the Study:
- To investigate if PGC-1α is a viable therapeutic target for heart failure.
- To assess the effects of moderate PGC-1α overexpression on mitochondrial biogenesis and cardiac function.
Main Methods:
- Utilized a transgenic mouse model with moderate cardiac PGC-1α overexpression (approx. 3-fold).
- Assessed baseline cardiac function, energetics, and mitochondrial parameters.
- Evaluated responses to dobutamine stress (in vivo) and high workload (ex vivo).
- Induced pressure overload using transverse aortic constriction (TAC) to study long-term effects on survival and cardiac function.
Main Results:
- Moderate PGC-1α overexpression led to minor increases in citrate synthase activity and mitochondria size without affecting baseline cardiac energetics or function.
- Dobutamine stress response was attenuated in transgenic mice.
- Transverse aortic constriction resulted in higher acute mortality in transgenic mice.
- Transgenic mice exhibited worsened cardiac dysfunction and increased left ventricular dimensions post-TAC, despite maintained mitochondrial gene expression and citrate synthase activity.
Conclusions:
- Moderate cardiac PGC-1α overexpression compromises acute survival during pressure overload.
- This level of PGC-1α overexpression does not improve cardiac function in a mouse model of chronic pressure overload.
- PGC-1α may not be an appropriate therapeutic target for increasing mitochondrial biogenesis in heart failure under these conditions.
