Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart

Lai, Ling; Leone, Teresa C.; Zechner, Christoph Peter Gerhard; Schaeffer, Paul J.; Kelly, Sean M.; Flanagan, Daniel; Medeiros, Denis M.; Kovács, Attila; Kelly, Daniel P.

doi:10.1101/gad.1661708

Cited by 299 publications

(351 citation statements)

References 57 publications

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“…However, RNAimediated down-regulation of PGC-1b in PGC-1a À/À preadipocyte lines additively inhibits mitochondrial respiration (Uldry et al, 2006). Similarly, mice lacking both PGC-1a and PGC1b show defective mitochondrial biogenesis and inhibited mitochondrial function in the heart and BAT (Lai et al, 2008). These studies indicate that PGC-1a and PGC-1b are partially functionally complementary.…”

Section: Introductionmentioning

confidence: 84%

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Sun

Feng

et al. 2012

Developmental Dynamics

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Background: Members of the PPARg coactivator-1 (PGC-1) family are central transcriptional coactivators that regulate cell metabolic processes ranging from mitochondrial biogenesis to oxidative respiration. PGC-1-related coactivator (PPRC1 or PRC), initially identified as a member of the PGC-1 family, is believed to regulate mitochondria biogenesis, respiration pathways, and cell proliferation. However, its physiological role is not clearly understood. Here, we investigate the biological functions of PPRC1 in vivo using PPRC1 deficient mice generated by gene targeting. Results: Homozygous deficient PPRC1 mice failed to form egg cylinders and died after implantation but before embryonic day 6.5, whereas mice heterozygous for PPRC1 were viable, fertile and indistinguishable from their wild-type littermates. Furthermore, PPRC1 mRNA was expressed at the embryonic stage before implantation and was rapidly upregulated during the first day of embryoid body formation. The PPRC1 mRNA was then subsequently down-regulated, although its precise function at this stage of development was unclear. Conclusions: This is the first study to suggest a nonredundant role for PPRC1 in mouse early embryonic development. Developmental Dynamics 241:975-983, 2012. V C 2012 Wiley Periodicals, Inc.Key words: embryonic lethality; gene targeting; PGC-1-related coactivator; PGC-1 family Key findings:Disruption of pprc1 gene causes peri-implantation embryonic lethality. Developmental deficiencies in pprc1 2/2 embryos occur during peri-implantation. In vitro culturing of pprc1 2/2 blastocysts is susceptible to growth retardation. PPRC1 mRNA is expressed during preimplantation embryonic development. PPRC1 mRNA is rapidly up-regulated during early embryoid body formation. Accepted 23 February 2012Developmental Dynamics ABBREVIATIONS PGC-1 PPARg coactivator-1 PPRC1 PGC-1-a-related coactivator protein BAT brown adipose tissue ICM inner cell mass TG trophoblast giant cells E3.5 embryonic day 3.5 ESC embryonic stem cell EB embryoid body

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Section: Introductionmentioning

confidence: 84%

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Sun

Feng

et al. 2012

Developmental Dynamics

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“…Generation of PGC-1␤ f/f mice was described previously (9). To generate adult cardiac-specific inducible PGC-1␣-and PGC-1␤-deficient mice, PGC-1␤ f/f mice were bred with mice expressing a mutated estrogen receptor-Cre recombinase fusion protein under control of the MHC promoter to specifically delete PGC-1␤ in the heart.…”

Section: Methodsmentioning

confidence: 99%

“…Adenoviral Infection-The adenoviral expression vectors Ad-PGC-1␣, Ad-PGC-1␤, and Ad-GFP have been described previously (9). The primary neonatal rat cardiac myocytes (NRCMs) were infected with adenovirus 24 h after differentiation and harvested 72 h post-infection.…”

Section: Methodsmentioning

confidence: 99%

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A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

Lai

Wang

Martin

et al. 2014

Journal of Biological Chemistry

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Background: Peroxisome proliferator-activated receptor ␥ coactivator 1 (PGC-1) ␣ and ␤ are transcriptional regulators of mitochondrial metabolism. Results: Loss of PGC-1 coactivators in mouse heart causes a defect in phospholipid biosynthesis resulting in mitochondrial ultrastructural abnormalities. Conclusion: PGC-1 coactivators coordinately regulate mitochondrial metabolism and structure. Significance: The mitochondrial phenotype of PGC-1-deficient mice resembles that of humans with genetic defects in mitochondrial phospholipid biosynthesis (Barth syndrome).

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“…Conversely, mice deficient in both Pgc‐1 α and Pgc‐1 β develop a perinatally lethal low cardiac output state and conduction disease 13. Cardiac phenotypes of mice lacking individual members of the PGC‐1 family are less severe.…”

Section: Introductionmentioning

confidence: 99%

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Ahmad

Valli

Salvage

et al. 2017

Clin Exp Pharma Physio

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SummaryIncreasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β−/− (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β−/− genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β−/− mice. Moreover, Pgc‐1β−/− mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β−/− mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β−/− systems in widespread cardiac regions.

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Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart

Cited by 299 publications

References 57 publications

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

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