Data on in vivo PGC-1alpha overexpression model via local transfection in aged mouse muscle.
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ABSTRACT:
SUBMITTER: Yeo D
PROVIDER: S-EPMC6301970 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Prolonged immobilization (IM) causes skeletal muscle atrophy characterized by mitochondrial deterioration and proteolysis. Muscle remobilization (RM) increases reactive oxygen species generation, proinflammatory cytokine expression, and oxidative stress, preventing muscle from quick recovery. Thus, we hypothesized that overexpression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) via in vivo transfection would promote mitochondrial biogenesis and antioxidant defense, thus ameliorating the aforementioned deteriorations in a mouse model with 14-d IM followed by 5-d RM. PGC-1α transfection in tibialis anterior muscle resulted in a 7.2- and 4-fold increase in PGC-1α content in cytosol and nucleus, respectively. Mitochondrial biogenic (cytochrome c, mitochondrial transcription factor A), morphologic (mitochondrial density, mDNA/nDNA ratio), and functional (cytochrome c oxidase activity, ATP synthesis rate) markers, as well as fiber cross-sectional area, significantly increased in IM-RM muscle by PGC-1α overexpression. These effects were accompanied by an 18% decrease in H2O2, 30% decrease in nuclear factor-κB-DNA binding, and 25% reduction of IL-1β and-6 production in IM-RM muscle. There was a 34% increase in superoxide dismutase-2 activity, along with a 3.5-fold increase in NAD-dependent deacetylase sirtuin-3 expression caused by enhanced PGC-1α-estrogen-related receptor α binding. Our findings highlighted the importance of PGC-1α in protecting muscle from metabolic and redox disturbances caused by IM.
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Project description:We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1alpha, PGC-1beta and oxidative fibers. Oxygen consumption, PGC-1alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1alpha resulted increased expression of PGC-1alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.
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Project description:Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1alpha from an alternate promoter. The induction of PGC-1alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1alpha. The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.
| S-EPMC2795492 | biostudies-literature
Project description:The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1α has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1α in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 α (HIF2α) as a major PGC-1α target in skeletal muscle that is positively regulated by both exercise and β-adrenergic signaling. This transcriptional regulation of HIF2α is completely dependent on the PGC-1α/ERRα complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2α target genes in primary myotubes suggested an unexpected role for HIF2α in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1α-mediated switch to slow, oxidative fibers in vitro is dependent on HIF2α, and mice with a muscle-specific knockout of HIF2α increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise.
| S-EPMC3003089 | biostudies-literature
Project description:Aging is a major risk factor for metabolic disease and loss of skeletal muscle mass and strength, a condition known as sarcopenia. Both conditions present a major health burden to the elderly population. Here, we analyzed the effect of mildly increased PGC-1alpha expression in skeletal muscle during aging. We found that transgenic MCK-PGC-1alpha animals had preserved mitochondrial function, neuromuscular junctions, and muscle integrity during aging. Increased PGC-1alpha levels in skeletal muscle prevented muscle wasting by reducing apoptosis, autophagy, and proteasome degradation. The preservation of muscle integrity and function in MCK-PGC-1alpha animals resulted in significantly improved whole-body health; both the loss of bone mineral density and the increase of systemic chronic inflammation, observed during normal aging, were prevented. Importantly, MCK-PGC-1alpha animals also showed improved metabolic responses as evident by increased insulin sensitivity and insulin signaling in aged mice. Our results highlight the importance of intact muscle function and metabolism for whole-body homeostasis and indicate that modulation of PGC-1alpha levels in skeletal muscle presents an avenue for the prevention and treatment of a group of age-related disorders.
| S-EPMC2787152 | biostudies-literature
Project description:The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1alpha. Overexpression of PGC-1alpha rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1alpha in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1alpha. Moreover, PGC-1alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.
| S-EPMC2504883 | biostudies-literature
Project description:The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of the mitochondrial and metatolic program in skeletal muscle (skm) and prevents atrophy. Here we tested whether PGC-1α overexpression could restructure the transcriptome and metabolism of cultured human skeletal myotubes, which display an athropic phenotype. An oligonucleotide microarray analysis was used to reveal PGC-1α effects on the whole transcriptome, and the possible impact on fuel metabolism reprogramming was examined. Fifty-three different genes displayed changed expression levels in response to PGC-1α: 42 upregulated and 11 downregulated. Main associations of gene ontologies (GO) for the upregulated genes were mitochondrial components and processes and this correlated with an increase in COX activity, an indicator of mitochondrial content. Palmitate and lactate oxidation to CO2 was enhanced, but not glucose oxidation. The other most significant GO associations of upregulated genes were chemotaxis and cytokine activity, and accordingly, several cytokines, including IL8, CXCL6, CCL5 and CCL8, were within top induced genes. Among the most regulated genes were also potential metabolic regulators of fatty acid and glucose storage. FITM1/FIT1 induction was associated with an increased number of lipid droplets with smaller area, while triglyceride levels were modestly increased in oleate-incubated cells. Downregulation of CALM1, the calcium-modulated δ subunit of phosphorylase kinase, was linked to inactivation of glycogen phosphorylase and greater accumulation of glycogen. The most upregulated gene was PVALB, which is also related to calcium signaling. In conclusion, only the deficient mitochondrial transcriptional program of cultured myotubes is rescued by PGC-1α. New PGC-1α gene targets and pathways arise, some of which may mediate its activating effects in processes such as lipid and carbohydrate storage and angiogenesis.
2012-03-15 | GSE28206 | GEO
Project description:Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1alpha mRNA but through HIF-1alpha protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1alpha is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.
| S-EPMC2632715 | biostudies-literature
Project description:We found that TLS can work as a PGC-1alpha cofactor and this assay was carried out to test the functional dependency of TLS on PGC-1alpha on a whole genome scale
2013-07-26 | GSE23242 | GEO
Project description:In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.
| S-EPMC1847661 | biostudies-literature