AMPKα stimulates skeletal muscle fatty acid utilization during in vivo exercise in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE61904 | GEO | 2015/09/30
SECONDARY ACCESSION(S): PRJNA262655
REPOSITORIES: GEO
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Project description:Metabolically healthy skeletal muscle is characterized by the ability to switch easily between glucose and fat oxidation, whereas loss of this ability seems to be related to insulin resistance. The aim of this study was to investigate whether different fatty acids (FAs) and the LXR ligand T0901317 affected metabolic switching in human skeletal muscle cells (myotubes). Pretreatment of myotubes with eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation, and metabolic flexibility, the ability to increase FA oxidation when changing from “fed” to “fasted” state. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was increased after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but did not affect these parameters alone. EPA itself accumulated less, however, EPA, LA, OA and T0901317 increased the number of lipid droplets (LDs) in myotubes, whereas LD size and mitochondria amount were independent of pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs. Some pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a possible favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Keywords: Analysis of target gene regulation by using microarrays. Primary human myotubes, derived from 3 healthy, female donors, were preincubated with different fatty acids (oleic acid [OA], palmitic acid [PA], eicosapentaenoic acid [EPA] or linoleic acid [LA], each at 100 µM) or bovine serum albumin [BSA] (40 µM) for 24 h.
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Project description:AMPKα stimulates skeletal muscle fatty acid utilization during in vivo exercise in mice
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Project description:Exercise stimulates systemic and tissue-specific adaptations that protect against lifestyle related diseases including obesity and type 2 diabetes. Exercise places high mechanical and energetic demands on contracting skeletal muscle, which require finely-tuned protein post-translational modifications involving signal transduction (e.g. phosphorylation) to elicit appropriate short- and long-term adaptive responses. To uncover the breadth of protein phosphorylation events underlying the adaptive responses to endurance exercise and skeletal muscle contraction, we performed global, unbiased mass spectrometry-based phosphoproteomic analyses of skeletal muscle from two rodent models, in situ muscle contraction in rats and treadmill-based endurance exercise in mice.
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Project description:Metabolically healthy skeletal muscle is characterized by the ability to switch easily between glucose and fat oxidation, whereas loss of this ability seems to be related to insulin resistance. The aim of this study was to investigate whether different fatty acids (FAs) and the LXR ligand T0901317 affected metabolic switching in human skeletal muscle cells (myotubes). Pretreatment of myotubes with eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation, and metabolic flexibility, the ability to increase FA oxidation when changing from “fed” to “fasted” state. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was increased after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but did not affect these parameters alone. EPA itself accumulated less, however, EPA, LA, OA and T0901317 increased the number of lipid droplets (LDs) in myotubes, whereas LD size and mitochondria amount were independent of pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs. Some pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a possible favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Keywords: Analysis of target gene regulation by using microarrays.
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Project description:Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, increases cardiovascular morbidity and mortality. We explore the relationship between dietary Pi excess and impaired exercise tolerance and physical inactivity. Analysis of the Dallas Heart Study shows association of higher serum Pi with reduced time spent in moderate to vigorous physical activity and increased sedentary time in humans. To test for causality, we investigated the impact of chronic exposure of high dietary Pi on exercise capacity in mice. Consumption of a high Pi diet for 3 months does not change the body weight but reduces maximal oxygen uptake, treadmill duration, and spontaneous locomotor activity, which is accompanied by substantial reduction in fat oxidation and fatty acid (FA) levels and downregulation of genes involved in FA synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Ppar in muscle. Similar results are recapitulated in in vitro by incubating C2C12 myotubes with high Pi media. In conclusion, our findings indicate that dietary phosphotoxicity reduces skeletal muscle FA metabolism and impairs exercise capacity independent of obesity, and may represent a novel and modifiable risk factor for cardiovascular disease.
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Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation
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