Targeted disruption of Slc2a8 (GLUT8) reduces motility and mitochondrial potential of spermatozoa

GLUT8 is a class 3 sugar transport facilitator which is predominantly expressed in testis and also detected in brain, heart, skeletal muscle, adipose tissue, adrenal gland, and liver. Since its physiological function in these tissues is unknown, we generated a Slc2a8 null mouse and characterized its phenotype. Slc2a8 knockout mice appeared healthy and exhibited normal growth, body weight development and glycemic control, indicating that GLUT8 does not play a significant role for maintenance of whole body glucose homeostasis. However, analysis of the offspring distribution of heterozygous mating indicated a lower number of Slc2a8 knockout offspring (30.5:47.3:22.1%, Slc2a8+/+, Slc2a8+/−, and Slc2a8−/− mice, respectively) resulting in a deviation (p=0.0024) from the expected Mendelian distribution. This difference was associated with lower ATP levels, a reduced mitochondrial membrane potential and a significant reduction of sperm motility of the Slc2a8 knockout in comparison to wild-type spermatozoa. In contrast, number and survival rate of spermatozoa were not altered. These data indicate that GLUT8 plays an important role in the energy metabolism of sperm cells.

[1]  C. Meyer,et al.  Ablation of the cholesterol transporter adenosine triphosphate-binding cassette transporter G1 reduces adipose cell size and protects against diet-induced obesity. , 2007, Endocrinology.

[2]  F. Middleton,et al.  Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa , 2006, Proceedings of the National Academy of Sciences.

[3]  J. Haefliger,et al.  GLUT8 Is Dispensable for Embryonic Development but Influences Hippocampal Neurogenesis and Heart Function , 2006, Molecular and Cellular Biology.

[4]  A. Schürmann,et al.  Endocytosis of the glucose transporter GLUT8 is mediated by interaction of a dileucine motif with the β2-adaptin subunit of the AP-2 adaptor complex , 2006, Journal of Cell Science.

[5]  W. Ford,et al.  Glycolysis and sperm motility: does a spoonful of sugar help the flagellum go round? , 2006, Human reproduction update.

[6]  K. Moley,et al.  GLUT8 Contains a [DE]XXXL[LI] Sorting Motif and Localizes to a Late Endosomal/Lysosomal Compartment , 2005, Traffic.

[7]  W. Willis,et al.  Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Marchetti,et al.  Comparison of four fluorochromes for the detection of the inner mitochondrial membrane potential in human spermatozoa and their correlation with sperm motility. , 2004, Human reproduction.

[9]  T. Doetschman,et al.  Targeted Ablation of Plasma Membrane Ca2+-ATPase (PMCA) 1 and 4 Indicates a Major Housekeeping Function for PMCA1 and a Critical Role in Hyperactivated Sperm Motility and Male Fertility for PMCA4* , 2004, Journal of Biological Chemistry.

[10]  P. Steiner,et al.  Regulated exocytosis of an H+/myo‐inositol symporter at synapses and growth cones , 2004, The EMBO journal.

[11]  M. J. Charron,et al.  Regulation of hepatic GLUT8 expression in normal and diabetic models. , 2003, Endocrinology.

[12]  G. Wennemuth,et al.  Bicarbonate actions on flagellar and Ca2+-channel responses: initial events in sperm activation , 2003, Development.

[13]  John Calvin Reed,et al.  Testis-Specific Cytochrome c-Null Mice Produce Functional Sperm but Undergo Early Testicular Atrophy , 2002, Molecular and Cellular Biology.

[14]  K. Moley,et al.  Glucose Transporter 8 Expression and Translocation Are Critical for Murine Blastocyst Survival1 , 2002, Biology of reproduction.

[15]  P. Marchetti,et al.  Study of mitochondrial membrane potential, reactive oxygen species, DNA fragmentation and cell viability by flow cytometry in human sperm. , 2002, Human reproduction.

[16]  P. Saftig,et al.  Reduced Sperm Count and Normal Fertility in Male Mice with Targeted Disruption of the ADP-Ribosylation Factor-Like 4 (Arl4) Gene , 2002, Molecular and Cellular Biology.

[17]  H. Axer,et al.  The glucose transport facilitator GLUT8 is predominantly associated with the acrosomal region of mature spermatozoa , 2002, Cell and Tissue Research.

[18]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[19]  A. Schürmann,et al.  Mouse GLUT8: genomic organization and regulation of expression in 3T3-L1 adipocytes by glucose. , 2001, Biochemical and biophysical research communications.

[20]  A. Schürmann,et al.  Targeting of GLUT6 (formerly GLUT9) and GLUT8 in rat adipose cells. , 2001, The Biochemical journal.

[21]  H. Joost,et al.  The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members , 2001, Molecular membrane biology.

[22]  Ying Cui,et al.  GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Andreas Brauers,et al.  GLUT8, a Novel Member of the Sugar Transport Facilitator Family with Glucose Transport Activity* , 2000, The Journal of Biological Chemistry.

[24]  M. Uldry,et al.  GLUTX1, a Novel Mammalian Glucose Transporter Expressed in the Central Nervous System and Insulin-sensitive Tissues* , 2000, The Journal of Biological Chemistry.

[25]  D. Froman,et al.  Reduced glucose transport in sperm from roosters (Gallus domesticus) with heritable subfertility. , 1997, Biology of reproduction.

[26]  R. Aitken,et al.  Comparative analysis of the ability of precursor germ cells and epididymal spermatozoa to generate reactive oxygen metabolites. , 1997, The Journal of experimental zoology.

[27]  X. Montagutelli,et al.  Male sterility caused by sperm cell-specific structural abnormalities in ebouriffé, a new mutation of the house mouse. , 1996, Biology of reproduction.

[28]  W. Krause.  Computer-assisted semen analysis systems: comparison with routine evaluation and prognostic value in male fertility and assisted reproduction. , 1995, Human reproduction.

[29]  L. Johnson,et al.  Viability assessment of mammalian sperm using SYBR-14 and propidium iodide. , 1995, Biology of reproduction.

[30]  C. Burant,et al.  GLUT3 glucose transporter isoform in rat testis: localization, effect of diabetes mellitus, and comparison to human testis. , 1994, The American journal of physiology.

[31]  S. Morgello,et al.  Tissue distribution of the human GLUT3 glucose transporter. , 1993, Endocrinology.

[32]  Regina M Turner,et al.  Moving to the beat: a review of mammalian sperm motility regulation. , 2006, Reproduction, fertility, and development.

[33]  M. Uldry,et al.  Immunolocalization of GLUTX1 in the testis and to specific brain areas and vasopressin-containing neurons. , 2002, Endocrinology.

[34]  D. Escalier,et al.  Pathology of the cytoskeleton of the human sperm flagellum: axonemal and peri‐axonemal anomalies , 1984, Biology of the cell.

[35]  Thomas D. Schmittgen,et al.  Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 2 DD C T Method , 2022 .