Rattus norvegicus
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PROVIDER: PRJNA395696 | ENA |
REPOSITORIES: ENA
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Project description:Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 177 experiments)
| PRJNA395695 | ENA
Project description:Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle
| PRJNA395691 | ENA
Project description:There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored in an in vitro L6 model. This model demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle model to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.
2017-07-26 | GSE101845 | GEO
Project description:There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored in an in vitro L6 model. This model demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle model to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.
2017-07-26 | GSE101844 | GEO
Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.
2012-02-04 | E-GEOD-34773 | biostudies-arrayexpress
Project description:Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
2023-05-08 | GSE224780 | GEO
Project description:Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor a), including expression of specific ESR1 variants is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males, and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.
2024-10-30 | GSE280715 | GEO
Project description:Here, we performed an in vitro toxicity assessment for remdesivir at clinically relevant concentrations around the cmax of 9 µM using H9c2 rat cardiomyoblasts and neonatal mouse cardiomyocytes (NMCM) as heart models and rat NRK-52E cells and human RPTEC/TERT1 cells as kidney models. Due to the tendency of nucleoside analogs for mitochondrial toxicity, we focused on metabolic changes and mitochondrial function. Additionally, we analyzed the functionality of NMCM and determined early proteomic changes.
2022-05-24 | PXD029311 | Pride
Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)
2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress
Project description:Mitochondrial functions are largely performed by proteins imported from cytosol. Impaired protein import in mitochondria affects the maintenance of intra-mitochondrial anabolic and energy metabolic pathways. It leads to cytosolic accumulation of mistargeted proteins and activation of cellular stress responses. To explore the communication between these mechanism in mammalian system, we targeted the co-chaperone of mitochondrial Hsp70, a GrpE Like protein 1 (Grpel1), in mice. We show that loss of protein import into mitochondrial matrix results in mitochondrial dysfunction, which triggers stress responses. The total shut down of mtHSP70 function by overall knockout of Grpel1 resulted in early embryonic lethality, and tamoxifen-induced skeletal muscle-specific knockout of Grpel1 caused rapid muscular atrophy. We show here, with transcriptomics analysis, that protein-import failure in mitochondria increased cellular proteotoxic stress due to mitochondrial dysfunction. As a control mechanism, it triggered adaptive stress responses, including unfolded protein responses and integrated stress responses. Metabolic profiling of skeletal muscle-specific knockout mice revealed amino acid and TCA cycle intermediates shuttle between serum and muscle.
2022-10-04 | GSE198540 | GEO