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Proteome and phosphoproteome analysis of skeletal muscle from Glut4 mutant mouse

ABSTRACT: This study aimed to investigate the effects of glucose restriction (GR) on energy metabolism and muscle fiber type in skeletal muscle. To achieve this goal, we created a mouse model of innate glucose limitation by mutating the major glucose transporter 4 (Glut4) in skeletal muscle. We performed proteomic and phosphoproteomic analyzes of gastrocnemius samples from 12-week-old male Glut4m mice, with or without low-intensity treadmill training.

ORGANISM(S): Mus Musculus

SUBMITTER: Shulin Yang

PROVIDER: PXD040294 | iProX | Tue Feb 21 00:00:00 GMT 2023

REPOSITORIES: iProX

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Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2.

Zhang Kaiyi K Xie Ning N Ye Huaqiong H Miao Jiakun J Xia Boce B Yang Yu Y Peng Huanqi H Xu Shuang S Wu Tianwen T Tao Cong C Ruan Jinxue J Wang Yanfang Y Yang Shulin S

iScience 20231129 1

Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechan ...[more]

PMID: 38161415

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Proteomic and phosphoproteomic analysis on skeletal muscle from Glut4 mutant mice

Project description:This study aimed to investigate the effect of glucose restriction (GR) on energy metabolism and muscle fibre type in skeletal muscle. To achieve this goal, we constructed a mouse model of innate glucose restriction by mutating the glucose transporter 4 (Glut4), the major glucose transporter in skeletal muscle. We performed proteomic and phosphoproteomic analysis on gastrocnemius samples of male Glut4m mice at 12-week age, with or without a 4-week low-intensity training.

2023-02-15 | PXD040132 |

The HDAC3 Enzymatic Activity Regulates Skeletal Muscle Fuel Metabolism

Project description:We address whether the functions of HDAC3 in skeletal muscle require its enzyme activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids (BCAAs) catabolism, and aging-associated reduction in muscle mass, without changes in the muscle fiber type composition or mitochondrial protein content. These findings demonstrate that the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity.

2018-11-30 | GSE115226 | GEO

Proteomic profiling on sex-specific changes on skeletal muscle after exercise

Project description:Biological sex-based differences are reported for aerobic capacity, exercise performance, skeletal muscle mass and fiber-type composition. We aimed to provide a yet missing comprehensive picture of molecular differences between female and male skeletal muscle before and during an 8-week exercise intervention. We characterized muscle biopsies from 25 (16f/9m) subjects with overweight and obesity in a multi-omics approach employing epigenomics, transcriptomics and proteomics at baseline, after acute exercise and after 8 weeks of supervised endurance training. Further we investigated which differences were conserved in myotubes obtained from these donors or can be restored by sex hormone treatment. We found differential CpG-site methylation in 16.012 genes, 1.366 differentially expressed genes and 120 differentially abundant proteins at baseline. Only non-autosomal gene expression was conserved in vitro. Part of sex-specific transcriptomic differences in vivo could be mimicked by sex hormone treatment in vitro. Differences in the proteome were dominated by higher abundance of proteins regulating glycogen degradation, glycolysis and of other fast-twitch fiber type proteins in males. Females showed higher abundance of proteins regulating fatty acid handling. The initial differences in fiber type-specific proteins were diminished after 8-week training, and both sexes adapted to endurance training by upregulating mitochondrial proteins involved in substrate oxidation and ATP production. Acute exercise upregulated stress-responsive transcripts predominantly in males. In conclusion, the sex-specific composition of the proteome underpins the differences in glucose and fatty acid metabolism in female and male skeletal muscle. Training mitigates these differences toward an endurance-trained proteomic profile in both sexes after only 8 weeks.

2025-09-02 | PXD058700 | Pride

Isolated fiber-type transcriptional profiles in human skeletal muscle

Project description:Skeletal muscle is a complex heterogeneous tissue comprised of diverse muscle fiber and non-fiber cell types that, in addition to movement, influences other systems such as immunity, metabolism and cognition. We investigated gene expression patterns of resident human skeletal muscle cells using both single-cell RNA-seq and RNA-seq of single muscle fiber dissections from vastus lateralis. We generated transcriptome profiles of the major multinucleated human skeletal muscle fiber-types as well as 11 human skeletal muscle mononuclear cell types, including immune, endothelial, pericyte and satellite cells. We delineated two fibro-adipogenic progenitor cell subtypes that may contribute to heterotopic ossification and muscular dystrophy fibrosis under pathological conditions. An important application of cell type signatures is for computational deconvolution of cell type specific gene expression changes using data from bulk transcriptome experiments. Analysis of transcriptome data from a 12 week resistance exercise training study using these human skeletal muscle cell-type signatures revealed significant changes in specific mononuclear cell-type proportions related to age, sex, acute exercise and training. This characterization of human skeletal muscle cell types will resolve cell-type specific changes in large-scale physical activity muscle transcriptome studies and can further the understanding of the diverse effects of exercise and the pathophysiology of muscle disease.

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Proteomics of slow and fast human muscle fibers reveals extensive fiber type-specific adaptations in response to exercise training

Project description:Skeletal muscle plays an important role in the health-promoting effects of exercise training, yet the underlying mechanisms are not fully elucidated. Proteomics of skeletal muscle is challenging due to presence of non-muscle tissues and existence of different fiber types confounding the results. This can be circumvented by analysis of pure fibers; however this requires isolation of fibers from fresh tissues. We developed a workflow enabling proteomics analysis of isolated muscle fibers from freeze-dried muscle biopsies and identified >4000 proteins. We investigated effects of exercise training on the pool of slow and fast muscle fibers. Exercise altered expression of >500 proteins irrespective of fiber type covering several metabolic processes, mainly related to mitochondria. Furthermore, exercise training altered proteins involved in regulation of post-translational modifications, transcription, Ca++ signaling, fat, and glucose metabolism in a fiber type-specific manner. Our data serves as a valuable resource for elucidating molecular mechanisms underlying muscle performance and health. Finally, our workflow offers methodological advancement allowing proteomic analyses of already stored freeze-dried human muscle biopsies.

2020-12-21 | PXD012824 | Pride

Single-cell transcriptional profiles in human skeletal muscle

Project description:Skeletal muscle is a complex heterogeneous tissue comprised of diverse muscle fiber and non-fiber cell types that, in addition to movement, influences other systems such as immunity, metabolism and cognition. We investigated gene expression patterns of resident human skeletal muscle cells using single-cell RNA-seq of dissections from vastus lateralis. We generate transcriptome profiles of 11 mononuclear human skeletal muscle mononuclear cell types, including immune, endothelial, pericyte and satellite cells. We delineate two fibro-adipogenic progenitor cell subtypes that may contribute to heterotopic ossification and muscular dystrophy fibrosis under pathological conditions. An important application of cell type signatures is for computational deconvolution of cell type specific changes using data from bulk transcriptome experiments. Analysis of transcriptome data from a 12 week resistance training study using the human skeletal muscle cell-type signatures revealed significant changes in specific mononuclear cell-type proportions related to age, sex, acute exercise and training. This characterization of human skeletal muscle cell subtypes will resolve cell type specific changes in large-scale physical activity muscle transcriptome studies and can further the understanding of the diverse effects of exercise and the pathophysiology of muscle disease.

2020-01-16 | GSE130646 | GEO

Effects of a 8-week training on human skeletal muscle

Project description:Context: Exercise training is a plausible model for identification of molecular mechanisms that cause metabolic-related changes in human skeletal muscle. Objective: The goal was to explore the molecular basis of the adaptation of skeletal muscle to exercise training. Design and Intervention: Obese male subjects were subjected to an individualized supervised training program targeted in order to optimize lipid oxidation during 8 weeks. Main Outcome Measures: Primary outcome measures were gene expression profiling of skeletal muscle. Body composition, oral glucose tolerance test, Resting metabolic rate, respiratory quotient, maximal oxygen uptake and metabolic biochemistry were also assessed.

2012-12-10 | GSE40551 | GEO

Gadd45a Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4

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

Beyond Myosin Heavy Chains in Human Skeletal Muscle Heterogeneity

Project description:Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, whether discrete fiber types exist or whether fiber heterogeneity reflects a continuum remains unclear. Furthermore, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from human vastus lateralis, respectively, we show that MYHs are not the principal drivers of skeletal muscle fiber heterogeneity. Instead, ribosomal heterogeneity drives the majority of variance between skeletal muscle fibers in a continual fashion, independent of slow/fast fiber type. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data challenge the concept that type 2X are phenotypically distinct from other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy. Our data question the currently accepted model of multiple distinct fiber types based on the expression of MYHs in humans and identifies ribosomal heterogeneity as a major driver of skeletal muscle fiber heterogeneity, opening a new field of research within skeletal muscle physiology.

2025-02-27 | PXD046863 | Pride

Impact of Aerobic Training on Transcriptomic Changes in Skeletal Muscle of Rats with Cardiac Cachexia

Project description:Cardiac cachexia (CC) is an advanced stage of heart failure (HF) characterized by structural and functional abnormalities in skeletal muscle, leading to muscle loss. Aerobic training provides benefits; however, the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the therapeutic effects of aerobic training on transcriptomic alterations associated with disease progression in cachectic skeletal muscle. HF was induced in male Wistar rats by a single monocrotaline injection (60mg/Kg). Aerobic training consisted of treadmill running for 30min at ~55% of maximal capacity, 5x/week for 4 weeks. Assessments included body mass, right ventricle mass, skeletal muscle fiber size and exercise tolerance. RNA sequencing analysis was per-formed on the medial gastrocnemius muscle. Sedentary cachectic rats exhibited 114 differentially expressed genes (DEGs) while exercised cachectic rats had only 18 DEGs compared to their respective controls. GO enrichment, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) identified key DEGs as po-tential hub genes involved in disrupted lipid metabolism and muscle remodeling in sedentary CC rats, which were not observed in the exercised CC rats. These findings suggest that aerobic training mitigates transcriptional alterations related to lipid me-tabolism and muscle remodeling in rats with CC, highlighting its therapeutic potential.

2025-07-16 | GSE298775 | GEO

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