Microarray skeletal muscle PGC-1alpha-/- - beta f/f/Mlc1fCre mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE23365 | GEO | 2010/12/01
SECONDARY ACCESSION(S): PRJNA131245
REPOSITORIES: GEO
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Project description:Title: Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity Abstract: Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α-/- βf/f/MLC-Cre mice) were generated and characterized. PGC-1α-/-βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α-/-βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α-/-βf/f/MLCCre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were also not altered in the PGC-1α-/-βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity. RNA from PGC-1alpha-/- beta f/f/Mlc1fcre was obtained and gene expression pattern compared with PGC-1alpha -/-, PGC-1beta f/f, and PGC-1beta f/f/Mlc1fCre controls. Results file descriptions: 1. GSE23365_skfloxAKO_PPexcl_genesup_GEO-8-16-2010: This table contains genes that were upregulated ≥2.0 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names. 2. GSE23365_skfloxAKO_PPexcl_genesdown_GEO-8-16-2010 This table contains genes that were downregulated ≤0.7 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names.
2010-12-01 | E-GEOD-23365 | biostudies-arrayexpress
Project description:Skeletal muscle insulin resistance and β-cell dysfunction are signature features of type 2 diabetes (T2D) pathogenesis. We previously demonstrated a pivotal role for the cell cycle kinase, Cdk4, in regulation of β-cell mass. Here, we demonstrate that Cdk4R/R mice, which harbor constitutively active Cdk4 kinase, are resistant to obesity and diabetes. The metabolic protection is associated with Cdk4 promoting the numbers and regeneration potential of slow/oxidative muscle fibers, improved muscle mitochondrial bioenergetics and elevated E2F3 and PGC-1α expression in muscle. In contrast, muscle-specific E2F3 knockout mice exhibit poor exercise capacity and susceptibility to obesity and diabetes. Exercise induces levels of Cdk4/E2F3/PGC-1α, while those levels are suppressed in obesity. Also, levels of E2F3/PGC-1α negatively correlate with adiposity, insulin resistance and lipid accumulation in human muscle biopsies. These findings are supportive of an important role for Cdk4/E2F3 in muscle fiber type development and metabolism with therapeutic potential for metabolic and muscular diseases.
2023-07-06 | GSE101820 | GEO
Project description:Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farensol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS farnesylation in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.
2023-08-12 | GSE240281 | GEO
Project description:Here we show that, when compared to control mice, muscle specific HuR knockout (muHuR-KO) animals have higher exercise endurance that is associated with a significant increase in oxygen consumption and carbon dioxide production. Histological analysis demonstrates that the absence of HuR significantly enhances the proportion of oxidative type I fibers in several skeletal muscles, showing that under normal conditions, HuR promotes the formation of glycolytic type II fibers. HuR mediates this outcome by collaborating with the mRNA decay factor KSRP, to destabilize the PGC-1α mRNA, a well-known promoter of type I fiber formation. Furthermore, the type I fiber-enriched phenotype of muHuR-KO mice is associated with a protection against cancer cachexia-induced muscle wasting
2019-08-21 | GSE134241 | GEO
Project description:Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA-sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift towards a slow MN identity. In muscle, NRTN increased capillary density, oxidative capacity, and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs, makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1ɑ1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.
2021-11-30 | GSE180266 | GEO
Project description:The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1 isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1 isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-12 and 3 are PGC-11 dimerization partners that limit its activity. Skeletal muscle PGC-12 and PGC-13 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1 loss-of-function. Mechanistically, PGC-11/3 dimerization precludes ERR recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-11 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training.
2022-05-21 | GSE203299 | GEO
Project description:It is known that both maternal and paternal health/disease can influence the early development and later metabolic homeostasis of the offspring. We investigated whether maternal exercise during gestation alone could protect the offspring from the adverse effects of either maternal or paternal obesity induced by high-fat diet (HFD). To understand the underlying mechanisms we performed transcriptomics, whole-genome DNA methylation and targeted DNA methylation analysis at the metabolic master regulator, peroxisome proliferator-activated receptor g coactivator-1a (Pgc-1a) promoter in the adult offspring skeletal muscle. Both maternal and paternal HFD resulted in impaired glucose tolerance in the offspring at 9 months of age. Maternal exercise during gestation completely mitigated this metabolic impairment induced by either maternal or paternal HFD. Adult offspring exposed to either maternal or paternal HFD without exercise during gestation had skeletal muscle transcriptional profiles enriched in genes regulating inflammation and immune responses, whereas maternal exercise resulted in a transcriptional profile that was more similar to control offspring from normal chow fed parents. Changes in promoter and CpG DNA methylation were detected between the groups but did not explain the transcriptional changes. Maternal HFD increased methylation of the Pgc-1α promoter at CpG -260, which was prevented by maternal exercise. Paternal HFD did not affect the methylation of the Pgc-1α promoter. These findings demonstrate the negative consequences of maternal and paternal obesity for the offspring’s metabolic outcomes later in life and the clear benefits of maternal exercise during gestation. The mechanisms involve transcriptional regulation of skeletal muscle likely through multiple types of epigenetic modifications.
2021-07-30 | GSE144111 | GEO
Project description:It is known that both maternal and paternal health/disease can influence the early development and later metabolic homeostasis of the offspring. We investigated whether maternal exercise during gestation alone could protect the offspring from the adverse effects of either maternal or paternal obesity induced by high-fat diet (HFD). To understand the underlying mechanisms we performed transcriptomics, whole-genome DNA methylation and targeted DNA methylation analysis at the metabolic master regulator, peroxisome proliferator-activated receptor g coactivator-1a (Pgc-1a) promoter in the adult offspring skeletal muscle. Both maternal and paternal HFD resulted in impaired glucose tolerance in the offspring at 9 months of age. Maternal exercise during gestation completely mitigated this metabolic impairment induced by either maternal or paternal HFD. Adult offspring exposed to either maternal or paternal HFD without exercise during gestation had skeletal muscle transcriptional profiles enriched in genes regulating inflammation and immune responses, whereas maternal exercise resulted in a transcriptional profile that was more similar to control offspring from normal chow fed parents. Changes in promoter and CpG DNA methylation were detected between the groups but did not explain the transcriptional changes. Maternal HFD increased methylation of the Pgc-1α promoter at CpG -260, which was prevented by maternal exercise. Paternal HFD did not affect the methylation of the Pgc-1α promoter. These findings demonstrate the negative consequences of maternal and paternal obesity for the offspring’s metabolic outcomes later in life and the clear benefits of maternal exercise during gestation. The mechanisms involve transcriptional regulation of skeletal muscle likely through multiple types of epigenetic modifications.
2021-07-30 | GSE144109 | GEO
Project description:Mitochondrial adaptations play a central role in the beneficial effects of exercise, particularly in metabolically active tissues such as skeletal muscle. Despite this, the molecular regulators of mitochondrial adaptive responses have not yet been fully elucidated. The long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) interacts with the master transcriptional regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In skeletal muscle of young healthy humans (n=14), we observed that TUG1 gene expression was elevated following an acute bout of continuous, moderate intensity cycling exercise and this positively correlated with PPARGC1A gene expression. Therefore, we hypothesised that TUG1 may modulate skeletal muscle mitochondrial responses to exercise. Knockdown (KD) of Tug1 in differentiating mouse myotubes resulted in altered mitochondrial morphology and impaired mitochondrial respiratory function, which was accompanied by greater myosin heavy chain slow isoform protein expression, despite lower Ppargc1a gene and MFN2 protein expression. Tug1 KD prevented the induction of Ppargc1a expression from a Ca2+ mediated stimulus (caffeine) yet the response to an AMPK agonist (AICAR ) was unaffected. RNA-sequencing revealed that Tug1 KD affected genes relating to mitochondrial Ca2+ transport and downstream targets of PGC-1α. Finally, in response to electrical pulse stimulation (EPS), an in vitro model of exercise in myotubes, there were ~300 genes whose upregulation in response to EPS was either blunted or augmented by Tug1 KD, including regulators of muscle differentiation and myogenesis. These data demonstrate that the lncRNA Tug1 is a novel regulator of skeletal muscle transcriptional responses to exercise and myogenesis.
2022-06-29 | GSE185530 | GEO
Project description:This experiment was conducted to identify target genes of the microRNA-499 in skeletal muscle of transgenic mice that overexpressed miR-499. The following abstract from the submitted manuscript describes the major findings of this work. Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. Jing Liu, Xijun Liang, Danxia Zhou, Ling Lai, Tingting Fu, Yan Kong, Qian Zhou, Rick B. Vega, Min-Sheng Zhu, Daniel P. Kelly, Xiang Gao, and Zhenji Gan. Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative type fibers. However, the mechanism for coupling of mitochondrial function to muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499 parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1a-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, a known AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1a. Inhibition of Fnip1 reactivated AMPK/PGC-1a signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function. Keywords: muscle, contractile fiber type, mitochondrial function, microRNA, gene regulation RNA from three wild-type (non-transgenic (NTG)) and three miR-499 overexpressing (MCK-miR-499) mice was analyzed. three replicates of each are provided.
2016-09-03 | E-GEOD-72581 | biostudies-arrayexpress