The effects of MuRF1 knockout, sex, and a high fat diet consumption on gastrocnemius muscle transcriptomics.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179163 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description:The effects of MuRF1 knockout, sex, and a high fat diet consumption on gastrocnemius muscle transcriptomics.
| PRJNA742471 | ENA
Project description:Under various pathophysiological muscle-wasting conditions like diabetes and starvation, a family of ubiquitin ligases, including MuRF1 (Muscle specific RING-Finger protein 1), are induced to target muscle proteins for degradation via ubiquitination. In an attempt to identify the in vivo targets of MuRF1 we have generated transgenic mouse lines overexpressing MuRF1 in a skeletal muscle specific fashion. MuRF1-TG lines were viable and had normal fertility. Characterization of their skeletal muscles did not reveal evidence for muscle wasting at 10 weeks of age. In this experiment we compared the skeletal muscle transcriptome of transgenic mice with wildtypes. Keywords: MuRF1 transgene overexpression
2008-05-15 | GSE10626 | GEO
Project description:MuRF1 is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Tibialis anterior (TA) muscles were transfected with an untagged MuRF1 plasmid or control plasmid for 14 days. A total of 963 ubiquitination sites, corresponding to 250 proteins, were quantified from the TA muscle. Statistical analysis revealed that the overexpression of MuRF1 resulted in significant upregulation of 153 ubiquitination sites on 45 proteins and significant downregulation of 16 sites on 11 proteins. Substrates of MuRF1 include contractile and metabolic proteins, deubiquitinases, p62, and VCP. Moreover, MuRF1-mediated ubiquitination leads to destabilization and breakdown of the sarcomere and reveals a role for MuRF1 in the regulation of additional proteolytic pathways in skeletal muscle.
2021-07-07 | PXD023872 | Pride
Project description:Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
2023-05-15 | PXD039151 | Pride
Project description:Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
2023-05-15 | PXD039158 | Pride
Project description:We previously identified a role for the muscle-specific ubiquitin ligase MuRF1 (Muscle Ring Finger-1) in cardiac ischemia-reperfusion (I/R) injury. We found that cardiomyocyte-specific (alphaMHC-) MuRF1 transgenic mice (MuRF1 Tg+) mice were significantly protected from I/R injury. As we discovered MuRF1’s regulation of other transcriptions factors, we sought to identify other ways in which MuRF1 was cardioprotective in I/R injury. In the present study, we first identified the regulation of MuRF1 expression by qPCR in a porcine model of I/R injury. MuRF1 mRNA significantly increased within 90 minutes of I/R injury. We next assayed MuRF1 Tg+ ventricular tissue after I/R reperfusion injury by microarray (44K transcripts) to identify how MuRF1 regulates the transcriptome. We identified 71 significantly altered genes having a >1.5-fold (p<0.01) in MuRF1 Tg+ and wildtype hearts challenged with I/R injury (or sham operation). Functional annotation of the top upregulated genes found enrichment for myogenesis, cell adhesion, and nucleic acid metabolism. TRANSFAC analysis of MuRF1 Tg+ significant genes identified enrichment for genes (30-53%) with promoter regions recognized by the transcription factors MAZ, PIT1, VMW65, and BACH2. The transcription factor MAZ binds muscle creatine kinase (MCK) promoter in skeletal and cardiac myocytes, known most for its regulation of myogenin and MEF2C in cardiomyocytes. While the role of PIT1 and BACH2 in adult cardiomyocytes is not clear, VMW65 is a powerful transactivator with functions in chromatin remodeling. In neonatal cardiomycoyte I/R injury, VMW65 associates with HIF1alpha to upregulate cardioprotective VEGF, Glut-1, Glut-4, HSP70, and iNOS expression. These findings elucidate the MuRF1-specific regulation of genes in cardiac I/R injury that are associated with cardioprotection and may represent multiple additional direct or indirect mechanisms that MuRF1 regulates cardiomyocyte signaling.
2019-01-05 | GSE108940 | GEO
Project description:Two genes coding for potential muscle signaling proteins were knocked out (MuRF1+2: DKO). RNA of hearts of Wildtype and DKO mice are compared to analyze the signaling pathwayws MuRF1 and MuRF2 are involved in.
2008-03-01 | E-MEXP-1027 | biostudies-arrayexpress
Project description:Introduction: The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle group has a specific composition and distribution of the four fiber types. Until now, three genes (CnA, PGC1α and PPARδ) are identified that are involved in the generation of more oxidative muscle types. In the present study we searched for novel genes that are involved in specifying different muscle types. Methods: Gastrocnemius and quadriceps muscles were dissected from 20-week old C57BL/6J mice. Gene expression profiles were compared at the level of the whole-transcriptome. The diet-sensitivity of genes differentially expressed between muscle types was explored by comparing mice fed a low fat diet with mice fed a high fat diet. Results: We identified 162 differentially expressed genes in the gastrocnemius as compared with the quadriceps. Genes with the strongest regulations were markers for oxidative fiber types, Hoxd8, Hoxd9 and Hoxd10 and others involved in embryogenesis. Additionally, diet did not influence the expression levels of genes specifying muscle types. Finally, when extrapolating our data to the soleus we could not find a corresponding gene expression pattern between Hoxd8, Hoxd9 and any of the fiber-type specific markers. However, based on these gene expression patterns we could distinguish the gastrocnemius, quadriceps and soleus from each other. Conclusion: Hoxd genes and genes that are markers for the different fiber types specify muscle type in a diet-independent way The aim of the present study was to find novel genes that may play a role in specifying muscle types. Therefore we compared gene expression profiles of the gastrocnemius with the quadriceps at the level of the whole-transcriptome. Functional implications were assessed by the analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways. muscle-type comparison
2010-09-03 | E-GEOD-18127 | biostudies-arrayexpress
Project description:To understand the role of LSD1 in transcriptional regulation in muscle under glucocorticoid stress, RNA-seq analyses of gastrocnemius and soleus muscles of skeletal muscle-specific LSD1 KO mice (LSD1-mKO mice) and WT mice after dexamethasone were carried out. We found that LSD1 inhibition led to increased expression of muscle atrophy associated genes and slow fiber genes in gastrocnemius muscle but not in soleus muscle.
2023-01-24 | GSE198826 | GEO
Project description:The processes by which mitochondria respond to cellular energy demands brought on by physiologic and pathophysiologic stimuli are essential to cellular adaptation and organismal survival. Disrupted mitochondrial function is implicated in several human disease states, underscoring the need to elucidate the molecular mechanisms that control mitochondrial function and metabolism. We previously described a patient with a gain-of-function mutation in Site-1 Protease (S1P) who exhibited idiopathic hyperCKemia, myoedema, and altered muscle mitochondrial morphology. To date, S1P has been heavily characterized in liver and bone, with very little known about its potential function in skeletal muscle. In our current study, we generated a skeletal muscle-specific S1P knockout mouse line (S1PsmKO) to examine the role of S1P in skeletal muscle. S1PsmKO mice were overtly normal in their appearance and health. However, examination of 12-week-old S1PsmKO mice showed increased gastrocnemius muscle mass and aged S1PsmKO mice exhibited increased muscle mass in both gastrocnemius and soleus relative to age-matched controls. Moreover, isolated muscle from S1PsmKO exhibited increased maximal mitochondrial respiration relative to floxed littermates (controls). RNA-Seq analysis showed increased transcript numbers of the mitochondrial-resident gene, Mss51 in S1PsmKO gastrocnemius relative to control mice. Mss51 is a member of the TGF-β/MSTN pathway, which controls mitochondrial metabolism. Similar to S1PsmKO muscle, S1P-depleted C2C12 cells also had increased maximal respiration, which was reversed by exogenous MSS51 expression. These data identify S1P as a regulator of muscle mass and mitochondrial metabolism, and implicate S1P as a novel modulator of TGF-β signaling. Method: Male mice were maintained on standard chow diet until 12 weeks of age.
2023-04-01 | GSE199014 | GEO