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Differential Expression of Zinc Transporters Accompanies the Differentiation of C2C12 Myoblasts

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Differential Expression of Zinc Transporters Accompanies the Differentiation of C2C12 Myoblasts University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2018-9 Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts Amanda L. Paskavitz University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Cell Biology Commons, Cells Commons, Developmental Biology Commons, and the Molecular Biology Commons Repository Citation Paskavitz AL, Quintana J, Cangussu D, Tavera-Montanez C, Xiao Y, Ortiz-Mirnada S, Navea JG, Padilla- Benavides T. (2018). Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts. Open Access Articles. https://doi.org/10.1016/j.jtemb.2018.04.024. Retrieved from https://escholarship.umassmed.edu/oapubs/3605 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Journal of Trace Elements in Medicine and Biology 49 (2018) 27–34 Contents lists available at ScienceDirect Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb Molecular biology Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts T Amanda L. Paskavitza,b,1, Julia Quintanac,2, Daniella Cangussua, Cristina Tavera-Montañeza,c, ⁎ Yao Xiaob, Sonia Ortiz-Mirandad, Juan G. Naveab, Teresita Padilla-Benavidesa, a Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605, USA b Department of Chemistry, Skidmore College, 815 North Broadway, Saratoga Springs, NY, 12866, USA c Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA, 01609, USA d Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605, USA ARTICLE INFO ABSTRACT Keywords: Zinc transporters facilitate metal mobilization and compartmentalization, playing a key role in cellular devel- Myogenesis opment. Little is known about the mechanisms and pathways of Zn movement between Zn transporters and Zinc metalloproteins during myoblast differentiation. We analyzed the differential expression of ZIP and ZnT trans- Zn-transporters porters during C2C12 myoblast differentiation. Zn transporters account for a transient decrease of intracellular Zn content Zn upon myogenesis induction followed by a gradual increase of Zn in myotubes. Considering the subcellular Gene Expression localization and function of each of the Zn transporters, our findings indicate that a fine regulation is necessary to maintain correct metal concentrations in the cytosol and subcellular compartments to avoid toxicity, maintain homeostasis, and for loading metalloproteins needed during myogenesis. This study advances our basic un- derstanding of the complex Zn transport network during muscle differentiation. 1. Introduction domains [2]. Zn transport occurs in response to an ionic gradient. Most ZnTs dimerize and export Zn by a diffusion-mediated Zn2+/H+ ex- Zinc (Zn) is an essential trace nutrient necessary for normal phy- change, while ZIPs import the ion through a channel-like activity [2]. siological functions in all forms of life [1,2]. Zn is a cofactor in up to However, some ZIPs import Zn through a bicarbonate/Zn2+ symport 10% of mammalian proteins and it is crucial for proper folding and for mechanism [11]. Certain transporters like ZIP8 and ZIP14 also trans- the catalytic activity of numerous enzymes [1,3]. With a Zn-deficient port Fe, Mn, and Cd [12] while ZnT10 is the only ZnT known to pri- diet, mammals develop anemia, growth retardation, hypogonadism, marily transport Mn over Zn [13,14]. skin abnormalities, diarrhea, neurological and mental deficiencies, Members of the ZnT and ZIP families have a prominent role in a alopecia, taste disorders, chronic inflammation and compromised im- wide range of developmental processes. For instance, in chondrocytes, mune function [1–6]. Conversely, excess Zn is cytotoxic and causes increased levels of cellular Zn have been associated with the presence of deficient copper absorption [7–9]. Therefore, cellular Zn homeostasis ZIP8 in lysosomal vesicles, which may activate MTF1, a metal re- must be tightly controlled. Two families of Zn transporters, ZnTs (so- sponsive transcription factor [15]. MTF1 in turn promotes the expres- lute-linked carrier 30, SLC30) and ZIPs (Zrt- and Irt-like proteins, sion of metalloproteases (MMPs) that degrade different components of SLC39) export and import Zn, respectively, between the cytosol, orga- the extracellular matrix [16–19]. ZIP12 has been found to induce neu- nelles, and extracellular milieu [1,2,10]. In mammals, ten ZnT (1–10) ronal differentiation via activation of cAMP response element binding exporters and fourteen ZIP importers (1-14) have been identified. protein (CREB) [20]. ZIP14 transports Fe, Mn and Cd in addition to Zn Nonetheless, the breadth of cellular functions for all these Zn trans- [21–23]. Interestingly, severely affected phenotypes are observed in porters remains to be elucidated. ZnTs and ZIPs are transmembrane Zip14 knock-out animals. For instance, these mice have impaired sys- proteins predicted to have 6 or 8 transmembrane domains, respectively temic growth, decreased body sizes, and impaired skeletal development [1,2]. ZnT5 is the exception, with nine putative transmembrane due to impaired CREB activation [24]. Moreover, mice lacking Zip14 ⁎ Corresponding author. E-mail address: [email protected] (T. Padilla-Benavides). 1 Current address: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. 2 Current address: Department of Molecular Genetics and Physiology of Plants, Ruhr University Bochum, Universitätsstrasse, 150, 44801, Bochum, Germany. https://doi.org/10.1016/j.jtemb.2018.04.024 Received 4 December 2017; Received in revised form 16 April 2018; Accepted 20 April 2018 0946-672X/ © 2018 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). A.L. Paskavitz et al. Journal of Trace Elements in Medicine and Biology 49 (2018) 27–34 present a proliferation defect in hepatocytes, are hypoglycemic, hy- lacks the distinguishing ZnT transmembrane Zn-binding domains and is perinsulinemic, and have higher levels of glucose in the liver [21,25]. mainly located in the cytoplasm [78,79]. ZnT9 acts as nuclear receptor Importantly, CREB activation is also necessary for proper development coactivator and was renamed as GAC63 [78]. and function of the skeletal muscle lineage. It is required for differ- In spite of all this accumulated research, little is known about Zn entiation of embryonic skeletal muscle progenitors, for survival of adult requirements, regulation, and distribution in differentiating skeletal skeletal muscle, for promoting myoblast proliferation in mice that were muscle cells. Because the majority of Zn in mammalian cells is bound to subject to muscle injury, and also for enhancing muscle regeneration in metalloenzymes and stored in organelles and cellular vesicles, free zinc a dystrophic mouse model [26]. ZIP2 is induced by Zn deprivation in levels remain quite low [2,80–84]. Within the cell, about 50% of Zn is monocytes, and is necessary for keratinocyte differentiation [1,27,28]. found in the cytoplasm and in vesicles, 30–40% in the nucleus, and Experimental evidence suggests a major role in development for ZIP2, about 10% in the cell membrane [85,86]. Moreover, 60% of the total as knock-out mice are sensitive to dietary Zn deficiency during preg- systemic Zn is sequestered and used in skeletal muscle, making this nancy [29]. ZIP5 is required for systemic Zn excretion and to promote organ the greatest reservoir of Zn in the body [87]. Whether Zn is ne- the development of the sclera and retina [30–32]. Zip6 over-expression cessary for myoblast differentiation is a matter of controversy. Experi- has been associated with the epithelial-mesenchymal transition of dif- mental evidence suggests that addition of Zn to differentiation medium ferent cancer types [33–37]. ZIP6 also contributes to dendritic cell inhibits myogenesis, but promotes myoblast proliferation and activa- maturation [38]. ZIP1 is proposed to be involved in activation of mi- tion of quiescent myogenic satellite cells [88]. Yet other evidence de- croglia, embryonic development, and prostate metabolism [2,39–42]. monstrated that Zn is required for differentiation, as myoblast differ- ZIP4 is required for early development, dietary Zn uptake in the in- entiation in both C2C12 cells and chicken embryo myoblasts was testine, and Zn levels regulate its expression [43,44]. ZIP10-dependent inhibited in Zn-deficient medium [88,89]. Furthermore, mice fed with a Zn signaling is required for early development of B-cells by suppressing Zn-deficient diet may have reduced muscle regeneration upon injury caspase activity in the bone marrow [45]. The above mentioned ZIPs [4]. C2C12 myoblasts are an excellent model to study myogenesis due are located to the plasma membrane. Other
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