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Temporal RNA-seq analysis of human skeletal myotubes synchronized in vitro

ABSTRACT: The circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. Extensive rhythmic transcription was observed in human skeletal muscle in comparison to in vitro cell culture. However, nearly half of the in vivo rhythmicity was lost at the mRNA accumulation level. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin stimulated glucose uptake were significantly reduced upon CLOCK depletion. Altogether, our findings suggest an essential role for cell-autonomous circadian clocks in coordinating muscle glucose homeostasis and lipid metabolism in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109825 | GEO | 2018/04/12

REPOSITORIES: GEO

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Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle

Project description:The circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. Extensive rhythmic transcription was observed in human skeletal muscle in comparison to in vitro cell culture. However, nearly half of the in vivo rhythmicity was lost at the mRNA accumulation level. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin stimulated glucose uptake were significantly reduced upon CLOCK depletion. Altogether, our findings suggest an essential role for cell-autonomous circadian clocks in coordinating muscle glucose homeostasis and lipid metabolism in humans.

2018-04-16 | GSE108539 | GEO

Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

Project description:Aims/hypothesis: Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms. Methods: We determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from men with either obesity or normal weight. Results: Palmitate reprogrammed the circadian transcriptome in myotubes without altering the mRNA rhythm of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. Cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment in myotubes. Chromatin immunoprecipitation and sequencing confirmed that palmitate altered the cycling of DNA regions associated with H3K27ac. Overlap of mRNA and DNA regions associated with H3K27ac and pharmacological inhibition of histone acetyl transferases revealed novel cycling genes associated to lipid exposure in human myotubes. Conclusion/interpretation: Palmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the circadian chromatin landscape and reprograms circadian gene expression of skeletal muscle.

2022-09-27 | GSE205424 | GEO

Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

2022-09-27 | GSE205677 | GEO

Transcriptomic and epigenomics atlas of myotubes reveals insight into the circadian control of metabolism and development [RRBS]

Project description:Aim: Innate circadian rhythms are critical for optimal tissue-specific functions, including skeletal muscle, a major insulin-sensitive tissue responsible for glucose homeostasis. We determined whether transcriptional oscillations are associated with CpG methylation changes in skeletal muscle. Materials & methods: We performed rhythmicity analysis on the transcriptome and CpG methylome of circadian synchronized myotubes. Results: We identified several transcripts and CpG-sites displaying oscillatory behavior, which were enriched with GO terms related to metabolism and development. Oscillating CpG methylation was associated with rhythmic expression of 31 transcripts. Conclusion: Although circadian oscillations may be regulated by rhythmic DNA methylation, strong rhythmic associations between transcriptome and CpG methylation were not identified. This resource constitutes a transcriptomic/epigenomic atlas of skeletal muscle and regulation of circadian rhythms.

2020-03-11 | GSE131843 | GEO

Transcriptomic and epigenomics atlas of myotubes reveals insight into the circadian control of metabolism and development [RNA-Seq]

2020-03-11 | GSE131842 | GEO

Effects of benfotiamine in cultured human myotubes exposed to both normal and high glucose cencentrations

Project description:The aim of the present work was to study the effects of benfotiamine (S-benzoylthiamine O-monophosphate) upon glucose and lipid metabolism and gene expression in differentiated human skeletal muscle cells (myotubes) incubated for 4 days under normal (5.5 mM glucose) and hyperglycemic (20 mM glucose) conditions. Myotubes established from lean, healthy volunteers were treated with benfotiamine for 4 days. Glucose and lipid metabolism were studied with labeled precursors. Gene expression was measured using real time polymerase chain reaction (qPCR) and microarray technology. Cell experiment, pared observations treated vs control, cells from 3 different donors

2011-08-21 | E-GEOD-31553 | biostudies-arrayexpress

Integration of Feeding Behaviour by the Liver Circadian Clock Reveals Network Dependency of Metabolic Rhythms [ChIP-seq]

Project description:The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

2021-06-01 | GSE169483 | GEO

Integration of Feeding Behaviour by the Liver Circadian Clock Reveals Network Dependency of Metabolic Rhythms [RNA-seq]

2021-06-01 | GSE171183 | GEO

Effects of benfotiamine in cultured human myotubes exposed to both normal and high glucose cencentrations

2011-08-22 | GSE31553 | GEO

Circadian misalignment induces fatty acid metabolism gene profiles and induces insulin resistance in human skeletal muscle.

Project description:Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes, however, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and muscle molecular circadian clock have never been investigated in humans. Here we investigated insulin sensitivity and muscle metabolism in fourteen healthy young lean men (age 22.4 ± 2.8 years; BMI 22.3 ± 2.1 kg/m2 [mean ± SD]) after a 3-day control protocol and a 3.5-day misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that circadian misalignment results in a significant decrease in peripheral insulin sensitivity due to a reduced skeletal muscle non-oxidative glucose disposal (Rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg/min; control vs. misalignment; p=0.024). Fasting glucose and FFA levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the new behavourial rhythm, and microarray analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misallignement. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers.

2018-08-10 | GSE106800 | GEO

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