Pantothenate kinase 4 controls skeletal muscle substrate metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1142866 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30070084_1.fastq.gz | Fastqsanger.gz | |||
| SRR30070084_2.fastq.gz | Fastqsanger.gz | |||
| SRR30070085_1.fastq.gz | Fastqsanger.gz | |||
| SRR30070085_2.fastq.gz | Fastqsanger.gz | |||
| SRR30070086_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl levels. These elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.
2024-10-24 | GSE273694 | GEO
Project description:Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote efficient energy metabolism. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in muscle. Germline deletion of Pank4 reduces circulating IGF-1 and stunts growth in mice. Muscle-specific deletion of Pank4 leads to a reduction in carnitzed and in impaired fatty acid oxidation in oxidative muscle which is related to higher acetyl-CoA and malonyl levels. Acetyl-CoA levels were persistently elevated in SkM lacking PanK4, independent of prandial state. In addition to perturbations of fatty acid oxidation, high SkM acetyl-CoA levels were associated with whole-body glucose intolerance, impaired insulin-stimulated glucose uptake into glycolytic SkM and impaired SkM glucose uptake during exercise. Conversely, we show that an increase in PanK4 lowers acetyl-CoA and increases glucose uptake in glycolytic SkM. Our findings identify PanK4 as a conserved exercise target that regulates SkM acetyl-CoA levels and plays a key role in lipid and glucose metabolism.
2024-10-25 | PXD057017 | Pride
Project description:Metabolic programming is a central regulator of T cell activation, differentiation and effector function. These metabolic processes are intricately linked to the anti-tumor properties of T cells and manipulation of T cell metabolism has shown promise in enhancing immunotherapy. To gain further insight into the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to interrogate the metabolic profile of three different CD8+ T cell subsets each with varying degrees of anti-tumor activity in murine models. These subsets include IFN-γ+ Tc1, IL-17+ Tc17 and IL-22+ Tc22 CD8+ effector subsets, of which Tc22 cells display the most robust anti-tumor activity. Here, we show that Tc22s were distinct in their up-regulation of the pantothenate/coenzyme A (CoA) pathway and requirement for oxidative phosphorylation (OXPHOS) for differentiation. Further investigation revealed that the exogenous administration of CoA metabolically reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). CoA-treated CD8+ T cells demonstrated enhanced anti-tumor function and persistence following adoptive transfer in murine tumor models. Treatment of mice with the CoA precursor pantothenate also enhanced the efficacy of anti-PD-L1 antibody therapy in preclinical models. These findings were extended to human melanoma patients, as we correlated increased pre-treatment plasma pantothenate levels with response to anti-PD1 antibody therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics and anti-tumor immunity.
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Project description:Gene expression in a mouse model of Pantothenate Kinase-Associated Neurodegeneration
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Project description:Pantothenate metabolism fuels T cell antitumor immunity
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Project description:Mycobacterium tuberculosis can use a proteasome to degrade proteins when they are post-translationally modified with prokaryotic ubiquitin-like protein (Pup). While pupylation is reversible, mechanisms regulating depupylation have not been identified. Here, we identify a depupylation regulator, CoaX, a pseudo-pantothenate kinase. Pantothenate synthesis enzymes were more abundant in a ∆coaX mutant, including PanB, a substrate of the Pup-proteasome system. Media supplementation with pantothenate decreased PanB levels in a coaX and Pup-proteasome system-dependent manner. In vitro, CoaX accelerated depupylation of Pup~PanB, while addition of pantothenate inhibited this reaction. Collectively, we propose CoaX contributes to proteasomal degradation of PanB by modulating depupylation of Pup~PanB in response to pantothenate levels.
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Project description:Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle fiber proteins that associate with Gadd45a as it induces skeletal muscle atrophy in living mice. We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, the MAP kinase kinase kinase MEKK4. Furthermore, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into way that skeletal muscle atrophy occurs at the molecular level.
2016-05-17 | MSV000079730 | MassIVE
Project description:Numerous leucine-rich repeat kinase 2 mutations identified throughout the protein are associated with Parkinson disease, however the activating G2019S kinase domain mutation is currently regarded as the most common cause of familial and sporadic forms of this disorder. Despite studies demonstrating the prominent role that its kinase activity plays in the pathobiology of leucine-rich repeat kinase 2, few substrates have been identified and only a subset of these have been linked to disease. Therefore, we utilized protein microarrays to screen over 9,000 human proteins in an unbiased radiometric assay for potential targets of the kinase. ProtoArrayM-bM-^DM-" Human Protein Microarrays v5.0 (Invitrogen, Carlsbad, CA, USA) were used following the manufactureM-bM-^@M-^Ys protocol (ProtoArray Kinase Substrate Identification Kit). Briefly, slides were equilibrated at 4C for 15 min before blocking in 1% BSA in PBS for 1 h at 4oC with gentle shaking. Recombinant G2019S or D1994A glutathione-S-transferase (GST)-LRRK2 (970-2527) (Invitrogen) was diluted to 50nM in 20mM Tris (pH 7.5), 10mM MgCl2, 1mM EGTA, 1mM Na3VO4, 5mM beta-glycerophosphate, 2mM DTT, 0.02% polysorbate 20, and 10 mCi /mL of [gamma- 33P]ATP (33 nM final concentration) in a total volume of 120uL. Slides were overlayed with buffer alone, or buffer containing G2019S or D1994A LRRK2, then covered with a coverslip and placed in a 50 mL conical tube for 1 h at 30oC. Afterwards, slides were washed with 0.5% SDS buffer and water followed by centrifugation. Dried slides were exposed to a PhosphorImager plate (Amersham Biosciences, Piscataway, NJ, USA), and scanned on a Storm 840 (Molecular Dynamics, Inc., Sunnyvale, CA, USA) at 50 microns.
2012-07-13 | E-GEOD-30496 | biostudies-arrayexpress
Project description:A Zeb1/Mitochondrial Creatine Kinase Metabolic Axis Controls Osteoclast Activation and Skeletal Remodeling
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Project description:Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder of coenzyme A homeostasis caused by defects in the mitochondrial pantothenate kinase 2. Patients with PKAN present with a progressive neurological decline and brain iron accumulation, but general energy balance and nutrition status among these patients has not been reported. To determine if defects in PANK2 change basic energy metabolism in humans, we measured body composition, resting energy expenditure, dietary intake, and blood metabolites among 16 subjects with PKAN. Subjects had a broad range of disease severity but, despite the essential role of coenzyme A in energy metabolism, the subjects had remarkably normal body composition, dietary intake and energy metabolism compared to population normal values. We did observe increased resting energy expenditure associated with disease severity, suggesting increased energy needs later in the disease process, and elevated urinary mevalonate levels.
| S-EPMC6059611 | biostudies-literature