Metabolic regulation of BCAAs and glycogen via IRF4 in skeletal muscle
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ABSTRACT:
PROVIDER: PRJNA562888 | ENA |
REPOSITORIES: ENA
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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
| PRJNA590273 | ENA
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: Not available
| S-EPMC7539189 | biostudies-literature
Project description:Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. Skeletal muscle expresses Dystrophin which is 2.26 Mbp in length; however, how long-distance transcription is achieved is totally unknown. We had discovered RNA-binding protein SFPQ preferentially binds to long pre-mRNAs and specifically regulates the cluster of neuronal genes > 100 kbp. Here we investigated the roles of SFPQ for long gene expression, target specificities, and also physiological functions in skeletal muscle. Loss of Sfpq selectively downregulated genes >100 kbp including Dystrophin and caused progressive muscle mass reduction and metabolic myopathy characterized by glycogen accumulation and decreased abundance of mitochondrial oxidative phosphorylation complexes. Functional clustering analysis identified metabolic pathway related genes as the targets of SFPQ. These findings indicate target gene specificities and tissue-specific physiological functions of SFPQ in skeletal muscle.
2019-03-18 | GSE126795 | GEO
Project description:A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in the prior exercised muscle. The molecular mechanisms underlying this well-known phenomenon remain elusive. Here we report that a single bout of exercise induces marked activation of glycogen synthase (GS) and AMP-activated protein kinase (AMPK) for several days beyond normalized muscle glycogen content in man. Acute muscle specific deletion of AMPK activity in mouse muscle abrogated the ability for glycogen supercompensation, providing genetic evidence that AMPK serves as essential driver for glycogen supercompensation. Muscle proteomic analyses revealed elevated glucose uptake capacity in the prior exercised muscle while key proteins in fat oxidation and glycolysis largely remained unchanged. The temporal order of these sustained cellular alterations induced by a single bout of exercise provide a mechanism to offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen, ultimately leading to muscle glycogen supercompensation.
2018-08-30 | PXD009196 | Pride
Project description:Background: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance. Methods: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and functionrelated proteins were analysed by immunoblotting or immunostaining. Results: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs 1.043 ± 0.040, **P=0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs 3.207 ± 0.2511, *P=0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs 4231 ± 90.29, ***P=0.0006; running time to exhaustion, 186.8 ± 8.027 vs 220.8 ± 3.156, **P=0.0028), as compared to those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs 0.535 ± 0.0194, **P=0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs 5.467 ± 0.1892, *P=0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs 3228 ± 149.8, ***P＜0.0001; running time to exhaustion, 225.5 ± 7.689 vs 163 ± 6.476, **P=0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo. Conclusions: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.
2023-10-01 | GSE242294 | GEO