title: Accelerated apoptotic death and in vivo turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2.
abstract: The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte death called eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Here, we explored whether MSK1/2 participates in the regulation of eryptosis. To this end, erythrocytes were isolated from mice lacking functional MSK1/2 (msk(-/-)) and corresponding wild-type mice (msk(+/+)). Blood count, hematocrit, hemoglobin concentration and mean erythrocyte volume were similar in both msk(-/-) and msk(+/+) mice, but reticulocyte count was significantly increased in msk(-/-) mice. Cell membrane PS exposure was similar in untreated msk(-/-) and msk(+/+) erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo such as hyperosmotic shock or energy depletion to significantly higher levels in msk(-/-) erythrocytes than in msk(+/+) erythrocytes. Cell shrinkage following hyperosmotic shock and energy depletion, as well as hemolysis following decrease of extracellular osmolarity was more pronounced in msk(-/-) erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled erythrocytes from circulating blood was faster in msk(-/-) mice. The spleens from msk(-/-) mice contained a significantly greater number of PS-exposing erythrocytes than spleens from msk(+/+) mice. The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lang
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Rosi
authors.initials: R
authors.lastname: Bissinger
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Abul
authors.initials: A
authors.lastname: Fajol
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Madhuri S
authors.initials: MS
authors.lastname: Salker
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.affiliation: Charité Medical University Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Zelenak
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Ghashghaeinia
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.|Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Shuchen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.|Department of Biochemistry, University of Agriculture, 38040 Faisalabad, Pakistan.
authors.forename: Kashif
authors.initials: K
authors.lastname: Jilani
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Lupescu
authors.affiliation: MRC Phosphorylation Unit, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.|Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
authors.forename: Kathleen M S E
authors.initials: KM
authors.lastname: Reyskens
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Ackermann
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.|nstitute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.affiliation: Department of Internal Medicine, University of Tübingen, Otfried-Müller-Straβe 10, 72076 Tübingen, Germany.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S4K1, Canada.|Centre for Innovation, Canadian Blood Services, 1280 Main Street West, Hamilton, Ontario L8S4K1, Canada.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheffield
authors.affiliation: MRC Phosphorylation Unit, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.|Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.|Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S4K1, Canada.|Centre for Innovation, Canadian Blood Services, 1280 Main Street West, Hamilton, Ontario L8S4K1, Canada.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Qadri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006400:Hematocrit; D006454:Hemoglobins; D006461:Hemolysis; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009996:Osmotic Fragility; D009997:Osmotic Pressure; D010718:Phosphatidylserines / Q000378:metabolism; D061251:Primary Cell Culture; D017701:Reticulocyte Count; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics*
chemical_list: D006454:Hemoglobins; D010718:Phosphatidylserines; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1