Metabolic regulation of BCAAs and glycogen via IRF4 in skeletal muscle
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA562888 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10043432.fastq.gz | Fastqsanger.gz | |||
| SRR10043433.fastq.gz | Fastqsanger.gz | |||
| SRR10043434.fastq.gz | Fastqsanger.gz | |||
| SRR10043435.fastq.gz | Fastqsanger.gz | |||
| SRR10043436.fastq.gz | Fastqsanger.gz |
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Project description:Skeletal muscle is not only a primary site for glucose uptake and storage, but also a reservoir for amino acids stored as protein. How the metabolism of these two fuels is coordinated in skeletal muscle is incompletely understood. Here, we demonstrate that interferon regulatory factor 4 (IRF4) integrate glucose and amino acids flux by regulating glycogen synthesis and branched-chain-amino acid (BCAA) metabolism in skeletal muscle. Mice with IRF4 specifically knocked out in skeletal muscle (MI4KO) showed elevated plasma BCAAs and skeletal muscle glycogen content, decreased adiposity and body weight, along with increased energy expenditure, remarkable improvements in glucose and insulin tolerance, and protection from diet-induced obesity (DIO). Loss of IRF4 caused downregulation of the mitochondrial branched-chain aminotransferase isozyme (BCATm) in myocytes, which encodes for the enzyme catalyzing the first step of BCAA metabolism. Lack of IRF4 also led to the upregulation of protein targeting to glycogen (PTG), which is associated with enhanced mitochondrial Complex II activity and mitochondria number. Additionally, overexpression of IRF4 in skeletal muscle caused obesity and reduced exercise capacity. Mechanistically, we found that IRF4 directly regulates both BCATm and PTG expression, and that overexpression of BCATm can partially reverse the effects of IRF4 deletion. These studies establish IRF4 as a novel driver of both glucose and BCAA metabolism in skeletal muscle.
2019-08-30 | GSE136623 | GEO
Project description:Exercise-induced fatigue and exhaustion have been an interesting area for many physiologists.Muscle glycogen is critical forphysical performance. However, how glycogen depletion is manipulated during exercise is not very clear. Our aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation ofexercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and increased glycogen content with unaltered triglyceride levels compared to control mice on chow diet. In contrast, mice overexpression of IRF4 display decreased exercise capacity and lower glycogen content. Mechanistically, IRF4 regulates glycogen-associated regulatory subunit protein targeting to glycogen (PTG) to manipulate glucose metabolism. Knockdown of PTG can reverse the effects imposed by the absence of IRF4in vivo. Our studies reveal a regulatory pathway including IRF4/PTG/glycogen synthesis that controlling exercise capacity.
2019-11-19 | GSE140633 | GEO
Project description:IRF4 in skeletal muscle regulates exercise capacity via PTG/glycogen pathway
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Project description:It is well established that obese animals and humans show deficiencies in skeletal muscle content and metabolism. However, the mechanisms under how skeletal muscle metabolism affects systemic energy homeostasis is not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species. We found an immune-responsive transcription factor interferon regulatory factor 4 (IRF4) was conserved to be increased in obese subjects from the three species (humans, non-human primates and mice). Thus, we demonstrated that loss of IRF4 specifically in skeletal muscle of mice showed protection against the metabolic effects of high-fat diet, with unexpected increased plasma and muscle branched-chain amino acid (BCAA) levels. Conversely, overexpression of skeletal muscle IRF4 caused obesity and insulin resistance, with decreased BCAA contents. Mechanistically, IRF4 can transcriptionally regulate branched-chain aminotransferase isozyme (BCATm) expression, and that overexpression of BCATm can reverse the effects of IRF4 depletion regarding to metabolic phenotypes. Further, we demonstrated ablation of IRF4 in skeletal muscle increased mitochondrial activity and glycogen synthesis in a BCATm- dependent manner. These studies establish IRF4 as a novel driver of BCAA metabolism via BCATm in skeletal muscle and may interpret the BCAAs paradox in obesity.
2024-07-29 | GSE181107 | GEO
Project description:In this study Guo et al. revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. Mice with skeletal muscle specific ablation of IRF4 show ameliorated liver steatosis, inflammation, and fibrosis, without changes in body weight on nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis of mouse serum suggested that follistatin-like protein 1 (FSTL1) might link the communication between muscle and liver. Dual luciferase assays showed that IRF4 could transcriptionally regulate FSTL1 and reconstitution of FSTL1 expression in muscle of F4MKO mice was sufficient to restore the liver pathology. Furthermore, co-culture experiments verified that FSTL1 exerts its function in hepatocyte, macrophage, and hepatic satellite cells through CD14 and DIP2A, CD14, DIP2A, respectively. In human, serum FSTL1 is increased in NASH patients, but the mRNA level of Fstl1 and its receptors are decreased in NASH liver biopsy, suggesting the increased serum FSTL1 is from skeletal muscle as studied in F4MKO mice. These data unveiled a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-DIP2A/CD14 in the pathogenesis of NASH.
2023-09-13 | PXD045324 | Pride
Project description:Inter-organ crosstalk has gained more and more attention recently. However, the mechanisms under this remain incompletely understood. Here, we revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. We studied that skeletal muscle specifically deleted IRF4 (F4MKO) mice showed ameliorated liver steatosis, inflammation and fibrosis, without changes in body weight on NASH diet. Proteomics analysis of serum suggested that follistatin-like protein 1 (FSTL1), as a myokine, might linked the communication between skeletal muscle and liver. Dual luciferase assays showed that IRF4 can transcriptionally regulated FSTL1 and reconstitution of FSTL1 expression in skeletal muscle of F4MKO mice, using adeno-associated virus, was sufficient to restore the liver pathology. Furthermore, we performed co-culture experiments to verify different receptors contribute to FSTL1’s function in different cell types of liver. Finally, we found serum FSTL1 level was positively correlated with NASH progression in human, whereas the mRNA level of Fstl1 and its receptors were downregulated in liver biopsy from NASH patients. These data reveal a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-receptors in the pathogenesis of NASH and implicate useful targets for the management of NASH.
2023-09-11 | GSE216378 | GEO
Project description:It is well established that obese animals and humans show deficiencies in skeletal muscle content and metabolism. However, the mechanisms under how skeletal muscle metabolism affects systemic energy homeostasis is not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species. We found an immune-responsive transcription factor interferon regulatory factor 4 (IRF4) was conserved to be increased in obese subjects from the three species (humans, non-human primates and mice). Thus, we demonstrated that loss of IRF4 specifically in skeletal muscle of mice showed protection against the metabolic effects of high-fat diet, with unexpected increased plasma and muscle branched-chain amino acid (BCAA) levels. Conversely, overexpression of skeletal muscle IRF4 caused obesity and insulin resistance, with decreased BCAA contents. Mechanistically, IRF4 can transcriptionally regulate branched-chain aminotransferase isozyme (BCATm) expression, and that overexpression of BCATm can reverse the effects of IRF4 depletion regarding to metabolic phenotypes. Further, we demonstrated ablation of IRF4 in skeletal muscle increased mitochondrial activity and glycogen synthesis in a BCATm- dependent manner. These studies establish IRF4 as a novel driver of BCAA metabolism via BCATm in skeletal muscle and may interpret the BCAAs paradox in obesity.
2023-12-12 | GSE180906 | GEO
Project description:Exercise-induced fatigue and exhaustion are interesting areas for many researchers. Muscle glycogen is critical for physical performance. However, how glycogen metabolism is manipulated during exercise is not very clear. The aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation of exercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and increased glycogen content with unaltered triglyceride levels compared to control mice on chow diet. In contrast, mice overexpression of IRF4 displays decreased exercise capacity and lower glycogen content. Mechanistically, IRF4 regulates glycogen-associated regulatory subunit protein targeting to glycogen (PTG) to manipulate glucose metabolism in skeletal muscle. Knockdown of PTG can reverse the effects imposed by the absence of IRF4 in vivo. These studies reveal a regulatory pathway including IRF4/PTG/glycogen synthesis on controlling exercise capacity.
| S-EPMC7539189 | biostudies-literature
Project description:Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis
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Project description:MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice may cause a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.
2024-08-09 | GSE274378 | GEO