Circadian Epigenomic Control of Skeletal Muscle Fuel Metabolism by HDAC3
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79696 | GEO | 2016/09/06
SECONDARY ACCESSION(S): PRJNA316721
REPOSITORIES: GEO
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Project description:We address the function of HDAC3 in skeletal muscle metabolism We performed HDAC3 ChIP-seq, RNA-seq, and GRO-seq in mouse muscles at different times of the day and compared between WT and HDAC3-depleted muscles.
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Project description:We address whether the functions of HDAC3 in skeletal muscle require its enzyme activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids (BCAAs) catabolism, and aging-associated reduction in muscle mass, without changes in the muscle fiber type composition or mitochondrial protein content. These findings demonstrate that the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity.
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Project description:The HDAC3 Enzymatic Activity Regulates Skeletal Muscle Fuel Metabolism
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Project description:Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism. HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids catabolism, and reduced muscle mass during aging, without changes in the muscle fiber-type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance.
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Project description:Krill oil is a dietary supplement derived from Antarctic krill; a small crustacean found in the ocean. Krill oil is a rich source of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid, as well as the antioxidant astaxanthin. The aim of this study was to investigate the effects of krill oil supplementation, compared to placebo oil (high oleic sunflower oil added astaxanthin), in vivo on energy metabolism and substrate turnover in skeletal muscle cells. Skeletal muscle cells (myotubes) were obtained before and after a 7-week krill oil or placebo oil intervention, and glucose and oleic acid metabolism and leucine accumulation, as well as effects of different stimuli in vitro, were studied in the myotubes. In vivo intervention with krill oil increased oleic acid oxidation and leucine accumulation in skeletal muscle cells, however no effects were observed on glucose metabolism. The krill oil-intervention-induced increase in oleic acid oxidation correlated negatively with changes in serum low-density lipoprotein (LDL) concentration. In addition, myotubes were also exposed to krill oil in vitro. The in vitro study revealed that 24 h of krill oil treatment increased both glucose and oleic acid metabolism, enhancing energy substrate utilization. Transcriptomic analysis comparing myotubes obtained before and after krill oil-supplementation identified differentially expressed genes associated with e.g. glycolysis/gluconeogenesis, metabolic pathways and calcium signaling pathway, while proteomic analysis demonstrated upregulation of e.g. LDL-receptor in myotubes obtained after krill oil intervention. These findings suggest that krill oil intervention promotes increased fuel metabolism and protein synthesis in human skeletal muscle cells, with potential implications for metabolic health.
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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.
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2021-03-30 | PXD025092 | Pride
Project description:In intact animals, time of drug administration may be an important factor influencing drug response. Our general goal seeks to incorporate circadian time into the study of corticosteroid regulated gene expression. This study is designed to examine fluctuations in gene expression in skeletal muscle within the 24 hour circadian cycle in normal animals. Circadian time is relevant to designing optimal corticosteroid dosing regimens. Since levels of endogenous steroid exhibit circadian fluctuations, it is our hypothesis that the expression of genes controlled by corticosteroids either directly or indirectly will also exhibit a circadian pattern in normal animals. Keywords: time series design
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