CDKN2A-CDK4-E2F3 dependent oxidative skeletal muscle fiber transition in myogenesis, movement, and metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185154 | GEO | 2023/07/06
REPOSITORIES: GEO
Similar Datasets
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: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
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
2016-09-03 | GSE72581 | GEO
Project description:Objective: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. Results: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the “fiber paradox”. Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo. Conclusion: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.
2024-01-26 | PXD045665 | Pride
Project description:The prevalence of the metabolic syndrome (MS) is rapidly increasing all over the world. Consequently, there is an urgent need for more effective intervention strategies. Both animal and human studies indicate that lipid oversupply to skeletal muscle can result in insulin resistance which is one of the charecteristices of the MS. C57BL/6J mice were fed a low fat (10 kcal%) palm oil diet or a high fat (45 kcal%; HF) palm oil diet for 3 or 28 days. By combining transcriptomics with protein and lipid analyses we aimed to better understand the molecular events underlying the early onset of the MS. Short-term HF-feeding led to altered expression levels of genes involved in a variety of biological processes including morphogenesis, energy metabolism, lipogenesis and immune function. Protein analysis showed increased levels of the myosin heavy chain, slow fiber type protein and the complexes II, III, IV and V of the oxidative phosphorylation. Furthermore, we observed that the main mitochondrial membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, contained more saturated fatty acids. Altogether, these results point to a morphological as well as a metabolic adaptation by promoting a more oxidative fiber type. We hypothesize that after this early adaptation, a continued transcriptional down-regulation of genes involved in oxidative phosphorylation will result in decreased oxidative capacity at a later stage. Together with increased saturation of phospholipids of the mitochondrial membrane this can result in decreased mitochondrial function which is a hallmark observed in insulin resistance and type 2 diabetes. Keywords: diet intervention and time course In the present study we investigated the short versus the long term effects of a high fat diet on the mouse muscle transcriptome by performing a genome-wide analysis of high fat diet-responsive genes. C57BL/6J mice were fed a low fat (LF) diet (10 kcal% palm oil) or a high fat (HF) diet (45 kcal% palm oil) for 3 or 28 days. Total RNA samples (n = 6 per diet per time point) were individually hybridised tot the Affymatrix mouse genome 430 2.0 array.
2007-11-30 | E-GEOD-8524 | biostudies-arrayexpress
Project description:Skeletal muscle is highly developed after birth, consisting of glycolytic fast- and oxidative slow-twitch fibers; however, the mechanisms of fiber type-specific differentiation are poorly understood. Here, we found an unexpected role for mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes resulted in the specific reduction of fast-twitch muscle fibers independently of respiratory function. Altered mitochondrial fission caused the activation of the Akt/mammalian target of rapamycin (mTOR) pathway via the mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescued the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor-15 was upregulated, which repressed fast-twitch fiber differentiation. Our findings reveal a novel role for mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.
2023-04-01 | GSE228362 | GEO
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.
2010-12-01 | GSE23365 | GEO
Project description:Skeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine if a mitochondrial myopathy is associated with adjustments in skelatal fiber type composition. These effects of drug induced mitochondrial dysfunction on skeletal muscle fiber type composition were analyzed in an animal model.
2012-10-18 | E-MEXP-3642 | biostudies-arrayexpress
Project description:Objective: Skeletal muscle is a heterogeneous and dynamic tissue that adapts to functional demands and substrate availability by modulating muscle fiber size and type. The concept of muscle fiber type relates to its contractile (slow or fast) and metabolic (glycolytic or oxidative) properties. Here, we tested whether disruptions in muscle oxidative catabolism are sufficient to prompt parallel adaptations in energetics and contractile protein composition.
Conclusion: The loss of mitochondrial long-chain fatty acid oxidation elicits an adaptive response involving conversion of oxidative muscle towards a metabolic profile that resembles a glycolytic muscle but that is not accompanied by changes in myosin heavy chain isoforms. These data suggest that shifts in muscle catabolism are not sufficient to drive shifts in the contractile apparatus but are sufficient to drive adaptive changes in metabolic properties.
2022-01-12 | PXD030896 | JPOST Repository
Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.
2010-11-29 | E-GEOD-19420 | biostudies-arrayexpress