The Unfolded Protein Response Mediates Adaptation to Exercise in Skeletal Muscle through a PGC-1α/ATF6α Complex

Wu, Jun; Ruas, Jorge L.; Estall, Jennifer L.; Rasbach, Kyle A.; Choi, Jang Hyun; Li, Ye; Boström, Pontus; Tyra, Heather M.; Crawford, Robert W.; Campbell, Kevin P.; Rutkowski, D. Thomas; Kaufman, Randal J.; Spiegelman, Bruce M.

doi:10.1016/j.cmet.2011.01.003

Cited by 262 publications

(366 citation statements)

References 29 publications

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“…4c,d). No change in the phosphorylation of STK25 was observed in cells treated with thapsigargin (a strong inducer of mammalian endoplasmic reticulum stress through perturbation of calcium homeostasis [26]), or by serum starvation for 20 h (Fig. 4e,f).…”

Section: Resultsmentioning

confidence: 99%

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle

et al. 2012

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Aims/hypothesis This study investigates the role of serine/ threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism. Methods The effect of depleting STK25 in muscle cells was studied by reducing the mRNA and protein content of this target in the rat myoblast cell line L6 by small interfering (si)RNA. The changes in the mRNA and protein levels of several members of the fatty acid oxidative and glucose metabolic pathways were measured by quantitative realtime (qRT)-PCR and western blot. The rate of palmitate oxidation and glucose uptake was measured after transfection with siRNA for Stk25. Expression of STK25 was also evaluated in skeletal muscle biopsies from 41 white Europid men and women with normal and impaired glucose tolerance and type 2 diabetes using qRT-PCR. Results We demonstrate that partial depletion of STK25 increases the expression of uncoupling protein 3 (Ucp3), accompanied by increased lipid oxidation, in myoblasts. In addition, a reduced level of STK25 enhances the expression of Slc2a1 (also known as Glut1), Slc2a4 (also known as Glut4) and hexokinase 2, and correspondingly, improves insulin-stimulated glucose uptake in muscle cells. Consistent with these results, significantly higher STK25 levels were observed in the skeletal muscle of type 2 diabetic patients, compared with individuals with normal glucose tolerance. Conclusions/interpretation This is the first study indicating a possible role for STK25 in the regulation of glucose and lipid metabolism in L6 myoblasts. This kinase appears to be an interesting new mediator to be evaluated for therapeutic intervention in type 2 diabetes and related complications, as controlled increase in lipid oxidation and insulin-stimulated glucose uptake in skeletal muscle is favourable and can restore energy balance in metabolically compromised states.

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Section: Resultsmentioning

confidence: 99%

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle

et al. 2012

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“…Relative mRNA levels were determined by normalizing to the acidic ribosomal phosphoprotein P0 (36B4) transcript (mouse and human) or the ribosomal protein L19 (RPL19) transcript (rat). The sequences of the primer sets used were previously shown (7,17,(26)(27)(28). Sequences of other primer sets used in this study were as follows: mouse asparagine synthetase (ASNS), 5D′-CAAGGAGGCCCAAGTTCAGTAT-3′ and 5′-GGCTG-TCCTCCATGCCAAT-3′; rat FGF21, 5′-CACCGCAGTCC-AGAAAGTCT-3′ and 5′-CATAGAGAGTTCCATCTGGTT-GTTG-3′; rat RPL19, 5′-CTCATGGAGCACATCCACAA-3′ and 5′-TGGTCAGCCAGTAGCTTCTTG-3′; rat C/EBP homologous protein (CHOP), 5′-TCCTGTCCTCAGAT-GAAATTGG-3′ and 5′-GGATGCAGGGTCAAGAGTA-GTG-3′; rat ASNS, 5′-GGAAGACAGCCCTGATCTAC-TG-3′ and 5′-TCATGATGCTCACTTCCAATATAATT-3′; rat FGF15, 5′-ACGGGCTGATTCGCTACTC-3′ and 5′-TG-TAGCCCAAACAGTCCATTTCCT-3′.…”

Section: Methodsmentioning

confidence: 99%

Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

Shimizu

Morimoto

Maruyama

et al. 2015

J Nutr Sci Vitaminol

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Summary Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor a (PPARa) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.

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“…The transcriptional coactivator PGC-1a, that regulates several exerciseassociated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6a. Efficient recovery from acute exercise is compromised in Atf6a-/-mice (Wu et al 2011). Thus, both ATF6 and XBP1, a transcriptional target of ATF6 that requires splicing by the endoribonuclease activity of IRE1, are considered as the predominant regulators of the adaptive UPR transcriptional response to resolve protein misfolding.…”

Section: Upr Signaling: Cell Survivalmentioning

confidence: 99%

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

Malhotra

Kaufman

2011

Cold Spring Harbor Perspectives in Biology

286

262

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The endoplasmic reticulum (ER) is the primary site for synthesis and folding of secreted and membrane-bound proteins. Proteins are translocated into ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to assist in proper folding. Properly folded proteins traffic from the ER to the Golgi apparatus; misfolded proteins are targeted to degradation. Unfolded protein response (UPR) is a highly regulated intracellular signaling pathway that prevents accumulation of misfolded proteins in the ER lumen. UPR provides an adaptive mechanism by which cells can augment protein folding and processing capacities of the ER. If protein misfolding is not resolved, the UPR triggers apoptotic cascades. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintain cellular homeostasis and determine cell fate under various pathophysiological conditions. Regulated Ca 2þ transfer from the ER to the mitochondria is important in maintaining control of prosurvival/prodeath pathways. We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes.T he ER is an elaborate membranous network present in all eukaryotic cells and responsible for many homeostatic responses that include folding and maturation of newly synthesized secretory and transmembrane proteins (Kleizen and Braakman 2004). In addition, this organelle is also the site of cholesterol and steroid biosynthesis, lipid biosynthesis, assembly of core-asparagine linked oligosaccharides, and membrane and secreted protein biosynthesis. Newly synthesized proteins require proper folding within the ER lumen prior to trafficking to specific destinations in the cell. These cellular processes are initiated when nascent polypeptide chains emerge in ER lumen, where posttranslational modifications such as N-linked glycosylation, and intra-and intermolecular disulfide bond formation facilitate the folding of polypeptides to form specific tertiary and quaternary structures for proper protein function (Molinari 2007). Although the amino acid sequence of the protein determines many

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The Unfolded Protein Response Mediates Adaptation to Exercise in Skeletal Muscle through a PGC-1α/ATF6α Complex

Cited by 262 publications

References 29 publications

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle

Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

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