FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA564102 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10073157_1.fastq.gz | Fastqsanger.gz | |||
| SRR10073157_2.fastq.gz | Fastqsanger.gz | |||
| SRR10073158_1.fastq.gz | Fastqsanger.gz | |||
| SRR10073158_2.fastq.gz | Fastqsanger.gz | |||
| SRR10073159_1.fastq.gz | Fastqsanger.gz |
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Project description:Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.
2019-09-05 | GSE136948 | GEO
Project description:Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.
| S-EPMC6385751 | biostudies-literature
Project description:Notch signaling plays essential roles in maintenance of muscle stem cell pool. We found that Notch2, but not Notch1 and Notch3, is expressed in fully differentiated myofibers. To study the specific role of Notch2 in adult myofibers, we generated muscle-specific Notch2-knockout mice. Here, we showed that muscle-specific Notch2 deficiency prevented muscle atrophy induced by hindlimb unloading and diabetes millitus. RNA sequencing analysis revealed that the loss of Notch2 gene in myofibers inhibited gene responses to unloading and diabetes. Especially, several FoxO-target genes and atrogenes were upregulated in wildtype muscles but not in Notch2-deficient muscles by unloading and diabetes. Thus, our characterization of muscle-specific Notch2-knockout mice indicates that Notch2 acts as a regulatory factor of skeletal muscle plasticity and could be a therapeutic target of muscle atrophy.
2022-01-07 | GSE161693 | GEO
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4. Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.
2014-08-20 | E-GEOD-60505 | biostudies-arrayexpress
Project description:Under stress conditions mammalian cells activate compensatory mechanisms to survive and maintain cellular function. During catabolic conditions, such as low nutrients, systemic inflammation, cancer or infections, protein breakdown is enhanced and aminoacids are released from muscles to sustain liver gluconeogenesis and tissues protein synthesis. Proteolysis in muscle is orchestrated by a set of genes named atrophy-related genes. A system that is activated both in short and prolonged stress conditions is the family of Forkhead Box (Fox) O transcription factors. Here, we report that muscle-specific deletion of FoxO members resulted in protection from muscle loss because FoxO family is required for induction of autophagy-lysosome and ubiquitin-proteasome systems. Importantly, FoxOs are required for Akt activity but not for mTOR signalling underlining the concept that FoxOs are upstream mTOR for the control of protein breakdown when nutrients are lacking. Moreover, FoxO family controls the induction of critical genes belonging to several fundamental stress response pathways such as unfolded protein response, ROS detoxification and translational regulation. Finally, we identify a set of novel FoxO-dependent ubiquitin ligases including the recent discovered MUSA11 and a new one, which we named Specific of Muscle Atrophy and Regulated by Transcription (SMART). Our findings identify the critical role of FoxO in regulating a variety of genes belonging to pathways important for stress-response under catabolic conditions. Gene expression in muscles of muscle-specific FoxO 1,3,4 knock-out mice that were fed normally or starved
2015-04-24 | GSE52667 | GEO
Project description:Under stress conditions mammalian cells activate compensatory mechanisms to survive and maintain cellular function. During catabolic conditions, such as low nutrients, systemic inflammation, cancer or infections, protein breakdown is enhanced and aminoacids are released from muscles to sustain liver gluconeogenesis and tissues protein synthesis. Proteolysis in muscle is orchestrated by a set of genes named atrophy-related genes. A system that is activated both in short and prolonged stress conditions is the family of Forkhead Box (Fox) O transcription factors. Here, we report that muscle-specific deletion of FoxO members resulted in protection from muscle loss because FoxO family is required for induction of autophagy-lysosome and ubiquitin-proteasome systems. Importantly, FoxOs are required for Akt activity but not for mTOR signalling underlining the concept that FoxOs are upstream mTOR for the control of protein breakdown when nutrients are lacking. Moreover, FoxO family controls the induction of critical genes belonging to several fundamental stress response pathways such as unfolded protein response, ROS detoxification and translational regulation. Finally, we identify a set of novel FoxO-dependent ubiquitin ligases including the recent discovered MUSA11 and a new one, which we named Specific of Muscle Atrophy and Regulated by Transcription (SMART). Our findings identify the critical role of FoxO in regulating a variety of genes belonging to pathways important for stress-response under catabolic conditions. Gene expression in muscles of muscle-specific FoxO 1,3,4 knock-out mice that were fed normally or starved We generated knocked-out FoxO 1,3,4 specifically in muscle by crossing FoxO1-3-4-floxed mice (FoxO1,3,4 f/f) with a transgenic line expressing Cre recombinase under the control of MLC1f promoter to generate muscle-specific FoxO1,3,4 triple knockout mice. These mice were either fed ad libitum or starved. Subsequently gene expression of the gastrocnemius muscles was analyzed. For each of the 4 conditions (FOXO1,3,4 f/f fed or starved, FOXO1,3,4-/- fed or starved), we isolated the gastrocnemius muscles of 3 mice thus yielding 6 muscles per condition. RNA was prepared from these muscles using the TRIzol method (Life Technologies) followed by cleanup with the RNeasy kit (QIAGEN). RNA concentration was determined by spectrophotometry and quality of the RNA was monitored using the Agilent 2100 Bioanalyzer (Agilent Technologies). RNA of the 6 muscles per condition was pooled equimolarly and used for further microarray analysis. cRNA was prepared, labelled and hybridised to Affymetrix Mouse Genome 430 2.0 Arrays using Affymetrix-supplied kits and according to standard Affymetrix protocols. Expression values were summarized using the Mas 5.0 algorithm. Genes that were up- or downregulated upon starvation compared to the fed condition were determined using Excel software. A threshold of 1.5 was used for the fold up-or downregulation consistent with the fold change that can be reliably detected with these type of arrays.
2015-04-24 | E-GEOD-52667 | biostudies-arrayexpress
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4.
2014-08-20 | GSE60505 | GEO
Project description:Forkhead BoxO (FoxO) transcription factors expressed in adult skeletal muscle promote muscle atrophy during various catabolic conditions. We have identified the genome wide target genes and biological networks regulated by FoxO in skeletal muscle during Colon-26 (C-26) cancer cachexia. In this dataset, we include the expression data obtained from the tibialis anterior muscles of control and severely cachectic Colon-26 mice in which FoxO-dependent transcription was either intact (AAV9-EV) or inhibited (AAV9-d.n.FoxO). These data were used to obtain 543 FoxO target genes during cancer. These target genes were identified as those genes whose expression was both differentially regulated in skeletal muscle in response to cancer (control AAV9-EV vs. C26 AAV9-EV), and differentially regulated in the presence of d.n.FoxO (C26 AAV9-EV vs. C26 AAV9-d.n.FoxO).
2014-12-31 | GSE56555 | GEO
Project description:To assess changes in the muscle proteome that due to tumor burden and dexamethasone treatments and compare proteomic changes that occur in atrophy due to tumor burden and dexamethasone treatment with atrophy caused by aging. Regulators of muscle atrophy induced by diseases such as cancer or drugs such as dexamethasone are largely unknown. We would therefore like to determine the proteomic signature of atrophying muscle caused by tumor burden (LLC cell injected mice) and dexamethasone treatment in order to examine possible biomarkers and regulators of muscle atrophy. We would also like to compared the proteomic signature of different modes of muscle atrophy to determine similarities and differences in the possible biomarkers and regulators.
2022-02-22 | PXD027490 | Pride
Project description:Notch2 deficiency prevents muscle atrophy induced by mechanical unloading and diabetes.
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