Dataset Information

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.

ABSTRACT:

Aims

Biological sex has fundamental effects on mammalian heart physiology and pathogenesis. While it has been established that female sex is a protective factor against most cardiovascular diseases (CVDs), this beneficial effect may involve pathways associated with cardiac energy metabolism. Our aim was to elucidate the role of transcriptional coactivator PGC-1α in sex dimorphism of heart failure (HF) development.

Methods and results

Here, we show that mice deficient in cardiac expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator-1α (PGC-1α) develop dilated HF associated with changes in aerobic and anaerobic metabolism, calcium handling, cell structure, electrophysiology, as well as gene expression. These cardiac changes occur in both sexes, but female mice develop an earlier and more severe structural and functional phenotype associated with dyssynchronous local calcium release resulting from disruption of t-tubular structures of the cardiomyocytes.

Conclusions

These data reveal that the integrity of the subcellular Ca2+ release and uptake machinery is dependent on energy metabolism and that female hearts are more prone to suffer from contractile dysfunction in conditions with compromised production of cellular energy. Furthermore, these findings suggest that PGC-1α is a central mediator of sex-specific differences in heart function and CVD susceptibility.

SUBMITTER: Naumenko N

PROVIDER: S-EPMC9074965 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.

Naumenko Nikolay N Mutikainen Maija M Holappa Lari L Ruas Jorge L JL Tuomainen Tomi T Tavi Pasi P

Cardiovascular research 20220501 6

<h4>Aims</h4>Biological sex has fundamental effects on mammalian heart physiology and pathogenesis. While it has been established that female sex is a protective factor against most cardiovascular diseases (CVDs), this beneficial effect may involve pathways associated with cardiac energy metabolism. Our aim was to elucidate the role of transcriptional coactivator PGC-1α in sex dimorphism of heart failure (HF) development.<h4>Methods and results</h4>Here, we show that mice deficient in cardiac ex ...[more]

PMID: 34086875

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Project description:UnlabelledHepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1α) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1α was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1α was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1α/L-PGC-1α and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1α isoforms promote HCV production in turn.ImportanceHCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1α (WT-PGC-1α), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV regulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. WT-PGC-1α upregulation was mediated by CREB phosphorylation, whereas L-PGC-1α upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1α/L-PGC-1α upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1α/L-PGC-1α and highlights the novel intervention of HCV-ER stress-PGC-1α signaling for HCV therapy and HCV-induced IR therapy.

Project description:BackgroundHeart failure (HF) is a complex clinical syndrome and a serious manifestation or late stage of various heart diseases. This study aimed to explore the protective effects and underlying mechanisms of Shenqi Lixin Decoction (SQLXD) in HF.MethodsA HF rat model was induced by intraperitoneal injection of adriamycin (3 mg/kg in the first 3 weeks, 2 mg/kg in the next 3 weeks, once a week, subcutaneous injection, 6 weeks cumulative dose is 15 mg/kg). After 4 weeks of intragastric administration of SQLXD (9.975, 19.95, 39.90 g/kg, once a day, gavage), the indexes of cardiac function were measured by cardiac color Doppler ultrasound, the cardiac muscle structure and pathological changes were observed by transmission electron microscope, hematoxylin-eosin (HE) staining and Masson. The plasma N-terminal B-type natriuretic peptide (NT-proBNP) level and myocardial tissue adenosine triphosphate (ATP) content were detected by ELISA. FITC detected the cardiomyocyte apoptosis rate (CMAR) labeled Annexin V/PI. Expression of B cell lymphoma factor 2 (Bcl-2), Bcl-2 associated X (Bax), cysteine protease-3 (Caspase-3), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA in myocardial tissue were detected by real-time PCR (RT-PCR). The expression of Bcl-2, Bax, Caspase-3 and P53 protein in myocardial tissue were detected by Western blot.ResultsCompared to the normal group, left ventricular end systolic diameter (LVSD), left ventricular end diastolic diameter (LVDD), CMAR and the expression of P53 protein, mRNA and protein of Bax and Caspase-3 were significantly increased in model group, while left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), stroke volume (SV) and the expression of Bcl-2 protein, mRNA of PGC-1α and Bcl-2 were significantly reduced. Compared to the model group, LVSD, LVDD, CMAR and the expressions of P53 protein, mRNA and protein of Bax and Caspase-3 in the medium and high dose SQLXD groups and the control group were significantly decreased, while LVEF, LVFS, SV and the expression of Bcl-2 protein, mRNA of PGC-1α and Bcl-2 were obviously increased. Pathological findings by transmission electron microscope, Masson, and HE staining all revealed protective effects of SQLXD on heart.ConclusionsSQLXD can effectively protect HF rats' hearts. The potential mechanism may be related to the modulation of the expression of PGC-1α and the mitochondrial apoptosis pathway.

Project description:The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.

Dataset Information

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.

Aims

Methods and results

Conclusions

Publications

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.

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