Similar Datasets
Project description:Metabolic rewiring is a well-established feature of muscle cells and a hallmark of cancer. In isocitrate dehydrogenase 1 and 2 mutant tumors, increased production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with myopathy. The connection between metabolic changes and proteomic remodeling in skeletal muscle remains poorly understood. We demonstrate that D2-HG impairs NAD+ redox homeostasis in myocytes, causing activation of autophagy via de-acetylation of microtubule-associated protein 1 light chain 3-II (LC3-II) by the nuclear deacetylase Sirt1. We integrated multi-omics data from mice treated with D2-HG and demonstrate that autophagy activation leads to skeletal muscle atrophy and sex-dependent metabolic and proteomic remodeling. We also characterized protein and metabolite interactions linking energy-substrate metabolism with chromatin organization and autophagy regulation. Collectively, our multi-omics approach exposes mechanisms by which the oncometabolite D2-HG induces metabolic and proteomic remodeling in skeletal muscle, and provides a conceptual framework for identifying potential therapeutic targets in cachexia.
2024-08-10 | PXD022137 | Pride
Project description:Oncometabolism Drives Autophagy Activation in Skeletal Muscle
| PRJNA670469 | ENA
Project description:Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
2023-01-20 | GSE222885 | GEO
Project description:Developmental and homeostatic remodeling of cellular organelles is mediated by a complex process termed autophagy. The cohort of proteins that constitute the autophagy machinery function in a multistep biochemical pathway. Though components of the autophagy machinery are broadly expressed, autophagy can occur in specialized cellular contexts, and mechanisms underlying cell type-specific autophagy are poorly understood. We demonstrate that the master regulator of hematopoiesis GATA-1 directly activates transcription of genes encoding the essential autophagy component Microtubule Associated Protein 1 Light Chain 3B (LC3B) and its homologs (MAP1LC3A, GABARAP, GABARAPL1, GATE-16). In addition, GATA-1 directly activates genes involved in the biogenesis/function of lysosomes, which mediate autophagic protein turnover. We demonstrate that GATA-1 utilizes the forkhead protein FoxO3 to activate select autophagy genes. GATA-1-dependent LC3B induction is tightly coupled to accumulation of the active form of LC3B and autophagosomes, which mediate mitochondrial clearance as a critical step in erythropoiesis. These results illustrate a novel mechanism by which a master regulator of development establishes a genetic network to instigate cell type-specific autophagy. Genome-wide maps of GATA1 factor occupancy in primary human PBMC derived erythroblasts
2011-09-30 | E-GEOD-32491 | biostudies-arrayexpress
Project description:MYTHO: a novel regulator of skeletal muscle autophagy and integrity mRNA expression data for the mouse muscle (n=4 per group) were obtained using Affymetrix Mouse Clariom S Assay (Affymetrix, Santa Carla, CA) according to the manufacturer’s recommendations.
2023-01-19 | GSE218706 | GEO
Project description:MYTHO: a novel regulator of skeletal muscle autophagy and integrity
| PRJNA923700 | ENA
Project description:molecular profiles (HG-U95B,C,D,E) of biopsy skeletal muscle samples obtained from 10 normal individuals and 10 DMD patients Keywords = gene expression profiles of normal human skeletal muscles Keywords = gene expression profiles of DMD patients' skelatal muscle samples Keywords = Affymetrix HG-U95B Keywords = Affymetrix HG-U95C Keywords = Affymetrix HG-U95D Keywords = Affymetrix HG-U95E Keywords: other
2004-02-04 | GSE1007 | GEO
Project description:Autophagy to apoptosis switching event is an unexplored area. We were interested to explore the gene expression profile at this juncture. Our Microarray data emphasized that among all eNOS and p62 genes were markedly induced. In fuctional level eNOS expression activates mTORC1 followed by inhibition of autophagy. This ultimately allowed accumulation of p62 . Intraccellular accumulation of p62 sequestered unfolded toxic protein aggregates in mitochondria and ER resulting in to impaired redox regulation. Intraccelular ROS generation further sensitized cells for apoptosis and tilted autophagic response to apoptosis. Cells were treated with Tunicamycin as an inducer of both autophagy and apoptosis. At early stage of Tunicamycin treatment 24h , prostate cancer cell PC3 showed activation of autophagic process where apoptosis was not evident. Sustained ER stress with Tunicamycin induced late apoptoisis at 72h of treatment. Hence we isolated total RNA from Untreated cells, cells with Tunicamycin treatment after 24h and 72h. Further the RNA were used to perform whole genome microarray to analyze the gene expression profile at autophagy and apoptosis juncture. The selected genes were also validated by qPCR and western bot. Morover RNAi study were implemented to evaluate the signaling crosstalk at the juncture of autophagy and apoptosis.
2014-05-22 | E-GEOD-38643 | biostudies-arrayexpress
Project description:Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSP) that lead to muscle weakness. Here, we identify METTL21C as a novel skeletal muscle-specific lysine methyltransferase. Insertion of a -galactosidase cassette into the Mettl21c mouse locus revealed METTL21C is specifically expressed in MYH7 positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to accumulation of cellular residuals due to incomplete autophagy in the skeletal muscle of Mettl21c-/- mutants during aging. Moreover, denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins in Mettl21c-/- muscles. In addition, we demonstrate METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We also reveal METTL21C trimethylates p97 on Lys315 residue, and found loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions due to its ability to trimethylate and regulate p97.
2018-05-04 | PXD008145 | Pride
Project description:The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain mysterious. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed the "V-ATPase-autophagy axis". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that the V-ATPase-autophagy axis is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates the V-ATPase-autophagy axis via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide a clear explanation for the mutational activation of autophagy seen in follicular lymphoma patients.
2025-03-11 | GSE290977 | GEO