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The RNA binding protein HuR influences skeletal muscle metabolic flexibility in rodents and humans

Published on Aug 1, 2019in Metabolism-clinical and Experimental6.513
· DOI :10.1016/j.metabol.2019.05.010
Randall L. Mynatt30
Estimated H-index: 30
(LSU: Louisiana State University),
Robert C. Noland19
Estimated H-index: 19
(LSU: Louisiana State University)
+ 6 AuthorsJaycob D. Warfel4
Estimated H-index: 4
(LSU: Louisiana State University)
Sources
Abstract
Abstract Background Metabolic flexibility can be assessed by changes in respiratory exchange ratio (RER) following feeding. Though metabolic flexibility (difference in RER between fasted and fed state) is often impaired in individuals with obesity or type 2 diabetes, the cellular processes contributing to this impairment are unclear. Materials and methods From several clinical studies we identified the 16 most and 14 least metabolically flexible male and female subjects out of >100 participants based on differences between 24-hour and sleep RER measured in a whole-room indirect calorimeter. Global skeletal muscle gene expression profiles revealed that, in metabolically flexible subjects, transcripts regulated by the RNA binding protein, HuR, are enriched. We generated and characterized mice with a skeletal muscle-specific knockout of the HuR encoding gene, Elavl1 (HuRm−/−). Results Male, but not female, HuRm−/− mice exhibit metabolic inflexibility, with mild obesity, impaired glucose tolerance, impaired fat oxidation and decreased in vitro palmitate oxidation compared to HuRfl/fl littermates. Expression levels of genes involved in mitochondrial fatty acid oxidation and oxidative phosphorylation are decreased in both mouse and human muscle when HuR is inhibited. Conclusions HuR inhibition results in impaired metabolic flexibility and decreased lipid oxidation, suggesting a role for HuR as an important regulator of skeletal muscle metabolism.
  • References (48)
  • Citations (1)
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References48
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#1Brent Holmes (UCLA: University of California, Los Angeles)H-Index: 9
#2Angelica Benavides-Serrato (UCLA: University of California, Los Angeles)H-Index: 6
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mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma
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#2Bolormaa Vandanmagsar (LSU: Louisiana State University)H-Index: 10
Last. Randall L. Mynatt (LSU: Louisiana State University)H-Index: 30
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Inhibiting fatty acid oxidation is one approach to lowering glucose levels in diabetes. Skeletal muscle specific Carnitine Palmitoyltransferase 1b knockout mice (Cpt1bm-/-) comprise a model of impaired fat oxidation; and have decreased fat mass and enhanced glucose disposal and muscle oxidative capacity compared to controls. However, unfavorable effects occur relative to controls when Cpt1bm-/- mice are fed a 25% fat diet, including decreased activity and fat free mass and increased intramuscula...
4 CitationsSource
#1Bret H. Goodpaster (Translational Research Institute)H-Index: 81
#2Lauren M. Sparks (Translational Research Institute)H-Index: 6
Metabolic flexibility is the ability to respond or adapt to conditional changes in metabolic demand. This broad concept has been propagated to explain insulin resistance and mechanisms governing fuel selection between glucose and fatty acids, highlighting the metabolic inflexibility of obesity and type 2 diabetes. In parallel, contemporary exercise physiology research has helped to identify potential mechanisms underlying altered fuel metabolism in obesity and diabetes. Advances in "omics" techn...
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Abstract Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nuc...
47 CitationsSource
#1Bolormaa Vandanmagsar (LSU: Louisiana State University)H-Index: 10
#2Jaycob D. Warfel (LSU: Louisiana State University)H-Index: 4
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Summary Fatty acids are the primary fuel source for skeletal muscle during most of our daily activities, and impaired fatty acid oxidation (FAO) is associated with insulin resistance. We have developed a mouse model of impaired FAO by deleting carnitine palmitoyltransferase-1b specifically in skeletal muscle ( Cpt1b m−/− ). Cpt1b m−/− mice have increased glucose utilization and are resistant to diet-induced obesity. Here, we show that inhibition of mitochondrial FAO induces FGF21 expression spec...
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Context: The role of perilipin 3 (PLIN3) on lipid oxidation is not fully understood. Objective: We aimed to 1) determine whether skeletal muscle PLIN3 protein content is associated with lipid oxidation in humans, 2) understand the role of PLIN3 in lipid oxidation by knocking down PLIN3 protein content in primary human myotubes, and 3) compare PLIN3 content and its role in lipid oxidation in human primary skeletal muscle cultures established from sedentary, healthy lean (leans), type 2 diabetic (...
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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonest...
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Skeletal muscle plays a relevant role in metabolic flexibility and fuel usage and the associated muscle metabolic inflexibility due to high-fat diets contributing to obesity and type 2 diabetes. Previous research from our group indicates that a high-fat and rapid-digesting carbohydrate diet during pregnancy promotes an excessive adipogenesis and also increases the risk of non-alcoholic fatty liver disease in the offspring. This effect can be counteracted by diets containing carbohydrates with si...
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The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these eff...
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