Expression, localization, and concentration of A-kinase anchor protein 4 (AKAP4) and its precursor (proAKAP4) in equine semen: Promising marker correlated to the total and progressive motility in thawed spermatozoa

Blommaert, D.; Sergeant, Nicolas; Delehedde, Maryse; Jouy, Nathalie; Mitchell, Valérie; Franck, Thierry; Donnay, Isabelle; Lejeune, Jean-Philippe; Serteyn, Didier

doi:10.1016/j.theriogenology.2019.03.011

Cited by 39 publications

(61 citation statements)

References 39 publications

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“…In the context of spermatozoa, the compartmentalization of cAMP signaling machinery coordinated by AKAP4 serves to regulate the specificity of signal transduction pathways responsible for the development, activation and maintenance of motility (Luconi et al, 2011;Sergeant et al, 2019). In accordance with this fundamental role, AKAP4 expression displays high evolutionary conservation, with Akap4 transcripts and/or immunoreactive orthologs of AKAP4 having been characterized in the testes and spermatozoa of species as phylogenetically diverse as eutherian mammals (humans, rodents, bovine, equine, porcine) (Johnson et al, 1997;Turner et al, 1998;Moss et al, 1999;Teijeiro and Marini, 2012;Blommaert et al, 2019;Sergeant et al, 2019), marsupials (tammar wallaby, opossum) (Hu et al, 2009), monotremes (platypus) (Hu et al, 2009), and reptiles (crocodile) (Nixon et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

“…These findings take on added significance in view of the dramatic under-representation of AKAP4 in the spermatozoa of infertile human patients (Moretti et al, 2007;Redgrove et al, 2012;Frapsauce et al, 2014). More recent work has also established positive correlations between the levels of AKAP4, and/or that of the proAKAP4 precursor molecule, with key sperm quality and fertility indicators in a number of livestock species (Peddinti et al, 2008;Blommaert et al, 2019;Sergeant et al, 2019). Taken together, these cross species analyses identify the potential use of proAKAP4 and AKAP4 as diagnostic biomarkers of overall semen quality (Sergeant et al, 2019).…”

Section: Introductionmentioning

confidence: 90%

“…Taken together, these cross species analyses identify the potential use of proAKAP4 and AKAP4 as diagnostic biomarkers of overall semen quality (Sergeant et al, 2019). At present however, it remains uncertain what factor(s) contribute to the striking differences in proAKAP4 and AKAP4 levels documented in livestock (Blommaert et al, 2019) and human spermatozoa (Jumeau et al, 2018). Here, we sought to validate proAKAP4 and AKAP4 as targets for chemical alkylation by 4HNE, and to explore the consequences of 4HNE-mediated alkylation of proAKAP4 and AKAP4 during key phases of sperm development.…”

Section: Introductionmentioning

confidence: 99%

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A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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Oxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly reactive lipid aldehyde elicits a spectrum of cytotoxic lesions owing to its propensity to form stable adducts with biomolecules. Notably however, not all elements of the sperm proteome appear to display an equivalent vulnerability to 4HNE modification, with only a small number of putative targets having been identified to date. Here, we validate one such target of 4HNE adduction, A-Kinase Anchor Protein 4 (AKAP4); a major component of the sperm fibrous sheath responsible for regulating the signal transduction and metabolic pathways that support sperm motility and capacitation. Our data confirm that both the precursor (proAKAP4), and mature form of AKAP4, are conserved targets of 4HNE adduction in primary cultures of post-meiotic male germ cells (round spermatids) and in mature mouse and human spermatozoa. We further demonstrate that 4HNE treatment of round spermatids and mature spermatozoa results in a substantial reduction in the levels of both proAKAP4 and AKAP4 proteins. This response proved refractory to pharmacological inhibition of proteolysis, but coincided with an apparent increase in the degree of protein aggregation. Further, we demonstrate that 4HNE-mediated protein degradation and/or aggregation culminates in reduced levels of capacitation-associated phosphorylation in mature human spermatozoa, possibly due to dysregulation of the signaling framework assembled around the AKAP4 scaffold. Together, these findings suggest that AKAP4 plays an important role in the pathophysiological responses to 4HNE, thus strengthening the importance of AKAP4 as a biomarker of sperm quality, and providing the impetus for the design of an efficacious antioxidant-based intervention strategy to alleviate sperm dysfunction.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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“…Emerging technologies based on biomolecules capable of predicting fertilization success and pinpointing the causative agents such as oxidative stress that can be targeted to prevent reproductive failure have recently been characterized [ 26 ]. A novel sperm protein and its precursor, AKAP4 and proAKAP4, respectively, have been previously established as molecular markers of sperm quality in different species (mice [ 46 ], stallions [ 47 ], boar [ 48 ], and humans [ 49 , 50 ]) due to their high correlation with sperm motility. AKAP4 and proAKAP4 are the most abundantly expressed proteins of the sperm fibrous sheath in all mammals, being part of the principle piece of the flagellum [ 51 , 52 , 53 ].…”

Section: Introductionmentioning

confidence: 99%

“…AKAP4 and proAKAP4 are the most abundantly expressed proteins of the sperm fibrous sheath in all mammals, being part of the principle piece of the flagellum [ 51 , 52 , 53 ]. Moreover, the proAKAP4 precursor molecule has recently emerged as a fertility indicator in a number of species such as humans, boar, and bulls [ 47 , 48 , 50 , 54 , 55 , 56 , 57 , 58 ] providing it with an added value as a diagnostic biomarker of overall semen quality.…”

Section: Introductionmentioning

confidence: 99%

ProAKAP4 as Novel Molecular Marker of Sperm Quality in Ram: An Integrative Study in Fresh, Cooled and Cryopreserved Sperm

et al. 2020

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To improve artificial insemination protocols in ovine species it is crucial to optimize sperm quality evaluation after preservation technologies. Emerging technologies based on novel biomolecules and related to redox balance and proteins involved in sperm motility such as ProAKAP4 could be successfully applied in ram sperm evaluation. In this work, a multiparametric analysis of fresh, cooled, and cryopreserved ram sperm was performed at different complexity levels. Samples were evaluated in terms of motility (total motility, progressive motility, and curvilinear velocity), viability, apoptosis, content of reactive oxygen species, oxidation‒reduction potential, and ProAKAP4 expression and concentration. As expected, cryopreserved samples showed a significant decrease of sperm quality (p < 0.05), evidencing different freezability classes among samples that were detected by ProAKAP4 analyses. However, in cooled sperm no differences were found concerning motility, viability, apoptosis, ROS content, and redox balance compared to fresh sperm that could explain the reported decrease in fertility rates. However, although the proportion of sperm ProAKAP4 positive-cells remained unaltered in cooled sperm compared to fresh control, the concentration of this protein significantly decreased (p < 0.05) in cooled samples. This altered protein level could contribute to the decrease in fertility rates of cooled samples detected by some authors. More importantly, ProAKAP4 can be established as a promising diagnostic parameter of sperm quality allowing us to optimize sperm conservation protocols and finally improve artificial insemination in ovine species.

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Downregulation of gene expression and the outcome of ICSI in severe oligozoospermic patients: A preliminary study

Sadakierska‐Chudy

Patrylak

Janeczko

et al. 2020

Molecular Reproduction Devel

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Preimplantation embryo development might be influenced by a specific set of transcripts that are delivered to the oocyte by the sperm. The aim of the study was to determine the relationship between the level of selected transcripts in spermatozoa and preimplantation development of the embryos in couples with severe oligozoospermia undergoing intracytoplasmic sperm injection (ICSI) procedure. Therefore, we assessed messenger RNA (mRNA) levels of genes involved in fertilization events, oocyte activation, chromatin remodeling, and DNA repair in severe oligozoospermic compared with normozoospermic men as well as morphokinetic parameters of embryos using the time-lapse imaging system. mRNA profiling (44 genes), in mature sperm, was carried out with custom-designed 384-well TLDA Cards. The morphokinetic parameters of zygotes and embryos were recorded by using a time-lapse imaging system. The transcript levels of 21 genes were significantly decreased in the severe oligozoospermic group. Most were associated with fertilization events, oocyte activation and embryonic genome activation. Among them, mRNA of AKAP4 and PTK7 was greatly reduced, moreover, the transcripts of PLCζ and POU5F1, essential for OA and EGA, were not detected at all in patients with severe oligozoospermia. Moreover, the reduced expression of genes important for spermatogenesis, chromatin remodeling and DNA repair was also observed in this group. Time-lapse analysis revealed that fertilization failure occurred in 14% of retrieved oocytes and 90% of all degenerated embryos did not reach morula stage. This study provides preliminary results indicating a significant decrease in transcripts of genes important for spermatogenesis and early preimplantation development in the mature sperm of men with severe oligozoospermia.

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Expression, localization, and concentration of A-kinase anchor protein 4 (AKAP4) and its precursor (proAKAP4) in equine semen: Promising marker correlated to the total and progressive motility in thawed spermatozoa

Cited by 39 publications

References 39 publications

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

ProAKAP4 as Novel Molecular Marker of Sperm Quality in Ram: An Integrative Study in Fresh, Cooled and Cryopreserved Sperm

Downregulation of gene expression and the outcome of ICSI in severe oligozoospermic patients: A preliminary study

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