Therapeutic Effect of Myostatin/Activin Blockage and Dietary Restriction in Modulation of Platelet Activation Markers of Progeroid Mouse Model
DOI:
https://doi.org/10.31185/wjps.833Keywords:
Ercc1Δ/- mice, Dietary restriction, Myostatin/activin blockade, GPIbα, P-SelectinAbstract
Aging-related decline in hematopoietic and platelet function is a hallmark of DNA repair deficiency syndromes, yet the impact of metabolic and pharmacological interventions on platelet biology in this context remains unclear. This study addresses this gap by investigating whether dietary restriction (DR) and myostatin/activin blockade through soluble Activin Receptor Type IIB (sActRIIB) can modulate platelet activation markers—GPIbα and P-Selectin—in a progeroid mouse model (Ercc1Δ/-). While DNA repair-deficient mice exhibited significantly reduced GPIbα expression compared to wild-type controls, sActRIIB treatment showed a modest, though non-significant, improvement. In contrast, DR alone or combined with sActRIIB had negligible effects. P-Selectin levels remained unchanged between mutant and control mice; however, sActRIIB treatment significantly suppressed its expression, indicating a potential anti-inflammatory effect. These findings suggest that myostatin/activin pathway inhibition may offer a partial therapeutic benefit in modulating platelet activation in progeroid models, whereas dietary restriction appears insufficient. It is important to conduct further studies to investigate specific, combinatorial application in the restoration of platelet homeostasis in DNA repair-deficient aging diseases.
References
[1] M. B. Birkisdóttir, I. van Galen, R. M. C. Brandt, S. Barnhoorn, N. van Vliet, C. van Dijk, B. Nagarajah, S. Imholz, C. T. van Oostrom, E. Reiling, Á. Gyenis, P. G. Mastroberardino, D. Jaarsma, H. van Steeg, J. H. J. Hoeijmakers, M. E. T. Dollé, and W. P. Vermeij, "The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside," Front Aging, vol. 3, p. 1005322, 2022. doi: 10.3389/fragi.2022.1005322 DOI: https://doi.org/10.3389/fragi.2022.1086552
[2] S. Xia, M. Wang, X. Mo, J. Wang, S. Zheng, and X. Shen, "Moderate dietary restriction across generations promotes sustained health and extends lifespan by enhancing antioxidant capacity in Bombyx mori," Scientific Reports, vol. 15, no. 1, p. 17533, 2025/05/20 2025. doi: 10.1038/s41598-025-02528-4 DOI: https://doi.org/10.1038/s41598-025-02528-4
[3] C. M. Gedik, G. Grant, P. C. Morrice, S. G. Wood, and A. R. Collins, "Effects of age and dietary restriction on oxidative DNA damage, antioxidant protection and DNA repair in rats," Eur J Nutr, vol. 44, no. 5, pp. 263-72, Aug 2005. doi: 10.1007/s00394-004-0520-0 DOI: https://doi.org/10.1007/s00394-004-0520-0
[4] M. Chimen, A. Evryviadou, C. L. Box, M. J. Harrison, J. Hazeldine, L. H. Dib, S. J. Kuravi, H. Payne, J. M. J. Price, D. Kavanagh, A. J. Iqbal, S. Lax, N. Kalia, A. Brill, S. G. Thomas, A. Belli, N. Crombie, R. A. Adams, S. A. Evans, H. Deckmyn, J. M. Lord, P. Harrison, S. P. Watson, G. B. Nash, and G. E. Rainger, "Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation," Haematologica, vol. 105, no. 5, pp. 1248-1261, May 2020. doi: 10.3324/haematol.2018.215145 DOI: https://doi.org/10.3324/haematol.2018.215145
[5] W. P. Vermeij, K. Alyodawi, I. van Galen, J. L. von der Heide, M. B. Birkisdóttir, L. J. Van't Sant, R. A. Ozinga, D. S. J. Komninos, K. Smit, Y. M. A. Rijksen, R. M. C. Brandt, S. Barnhoorn, D. Jaarsma, S. Vaiyapuri, O. Ritvos, T. B. Huber, O. Kretz, and K. Patel, "Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice," J Cachexia Sarcopenia Muscle, vol. 15, no. 6, pp. 2361-2374, Dec 2024. doi: 10.1002/jcsm.13570 DOI: https://doi.org/10.1002/jcsm.13570
[6] R. W. Hart and A. Turturro, "Dietary restrictions and cancer," Environmental Health Perspectives, vol. 105, no. suppl 4, pp. 989-992, 1997/06/01 1997. doi: 10.1289/ehp.97105s4989 DOI: https://doi.org/10.1289/ehp.97105s4989
[7] K. S. Iyer and S. Dayal, "Modulators of platelet function in aging," Platelets, vol. 31, no. 4, pp. 474-482, 2020. doi: 10.1080/09537104.2019.1665641 DOI: https://doi.org/10.1080/09537104.2019.1665641
[8] J. Peng, P. Friese, E. Heilmann, J. N. George, S. A. Burstein, and G. L. Dale, "Aged platelets have an impaired response to thrombin as quantitated by P-selectin expression," Blood, vol. 83, no. 1, pp. 161-166, 1994. doi: 10.1182/blood.V83.1.161.161 DOI: https://doi.org/10.1182/blood.V83.1.161.161
[9] R. Yan, Y. Xia, K. Zhou, J. Liu, Y. Sun, C. He, X. Ge, M. Yang, C. Sun, and L. Yuan, "Essential role of glycoprotein Ibα in platelet activation," Blood Advances, vol. 8, no. 13, pp. 3388-3401, 2024. doi: 10.1182/bloodadvances.2023012308
[10] M. K. Poddar and S. Banerjee, "Molecular Aspects of Pathophysiology of Platelet," Platelets, p. 21, 2020. doi: 10.5772/intechopen.92856 DOI: https://doi.org/10.5772/intechopen.92856
[11] R. P. Ertl, J. Chen, C. M. Astle, T. M. Duffy, and D. E. Harrison, "Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated," Blood, vol. 111, no. 3, pp. 1709-16, Feb 1 2008. doi: 10.1182/blood-2007-01-069807 DOI: https://doi.org/10.1182/blood-2007-01-069807
[12] K. E. O'Connell, W. Guo, C. Serra, M. Beck, L. Wachtman, A. Hoggatt, D. Xia, C. Pearson, H. Knight, M. O'Connell, A. D. Miller, S. V. Westmoreland, and S. Bhasin, "The effects of an ActRIIb receptor Fc fusion protein ligand trap in juvenile simian immunodeficiency virus-infected rhesus macaques," Faseb j, vol. 29, no. 4, pp. 1165-75, Apr 2015. doi: 10.1096/fj.14-257543 DOI: https://doi.org/10.1096/fj.14-257543
[13] G. Weeda, I. Donker, J. de Wit, H. Morreau, R. Janssens, C. J. Vissers, A. Nigg, H. van Steeg, D. Bootsma, and J. H. Hoeijmakers, "Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence," Curr Biol, vol. 7, no. 6, pp. 427-39, Jun 1 1997. doi: 10.1016/s0960-9822(06)00190-4 DOI: https://doi.org/10.1016/S0960-9822(06)00190-4
[14] J. Chen, J. A. Schroeder, X. Luo, R. R. Montgomery, and Q. Shi, "The impact of GPIbα on platelet-targeted FVIII gene therapy in hemophilia A mice with pre-existing anti-FVIII immunity," J Thromb Haemost, vol. 17, no. 3, pp. 449-459, Mar 2019. doi: 10.1111/jth.14379 DOI: https://doi.org/10.1111/jth.14379
[15] L. Nicolai, R. Kaiser, R. Escaig, M. L. Hoffknecht, A. Anjum, A. Leunig, J. Pircher, A. Ehrlich, M. Lorenz, H. Ishikawa-Ankerhold, W. C. Aird, S. Massberg, and F. Gaertner, "Single platelet and megakaryocyte morpho-dynamics uncovered by multicolor reporter mouse strains in vitro and in vivo," Haematologica, vol. 107, no. 7, pp. 1669-1680, Jul 1 2022. doi: 10.3324/haematol.2021.278896 DOI: https://doi.org/10.3324/haematol.2021.278896
[16] J. Tsao, D. A. Vernet, R. Gelfand, I. Kovanecz, G. Nolazco, K. W. Bruhn, and N. F. Gonzalez-Cadavid, "Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle," Stem Cell Res Ther, vol. 4, no. 1, p. 4, Jan 7 2013. doi: 10.1186/scrt152 DOI: https://doi.org/10.1186/scrt152
[17] I. Morianos, G. Papadopoulou, M. Semitekolou, and G. Xanthou, "Activin-A in the regulation of immunity in health and disease," Journal of Autoimmunity, vol. 104, p. 102314, 2019/11/01/ 2019. doi: https://doi.org/10.1016/j.jaut.2019.102314 DOI: https://doi.org/10.1016/j.jaut.2019.102314
[18] F. D. Bromer, A. Lodberg, M. Eijken, C. B. F. Andersen, M. F. Poulsen, J. S. Thomsen, and A. Brüel, "The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice," J Cachexia Sarcopenia Muscle, vol. 16, no. 1, p. e13718, Feb 2025. doi: 10.1002/jcsm.13718 DOI: https://doi.org/10.1002/jcsm.13718
[19] W. P. Vermeij, M. E. Dollé, E. Reiling, D. Jaarsma, C. Payan-Gomez, C. R. Bombardieri, H. Wu, A. J. Roks, S. M. Botter, B. C. van der Eerden, S. A. Youssef, R. V. Kuiper, B. Nagarajah, C. T. van Oostrom, R. M. Brandt, S. Barnhoorn, S. Imholz, J. L. Pennings, A. de Bruin, Á. Gyenis, J. Pothof, J. Vijg, H. van Steeg, and J. H. Hoeijmakers, "Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice," Nature, vol. 537, no. 7620, pp. 427-431, Sep 15 2016. doi: 10.1038/nature19329 DOI: https://doi.org/10.1038/nature19329
[20] A. T. Nurden and P. Nurden, "Inherited thrombocytopenias: history, advances and perspectives," Haematologica, vol. 105, no. 8, pp. 2004-2019, Aug 2020. doi: 10.3324/haematol.2019.233197 DOI: https://doi.org/10.3324/haematol.2019.233197
[21] N. G. Clavere, A. Alqallaf, K. A. Rostron, A. Parnell, R. Mitchell, K. Patel, and S. Y. Boateng, "Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling," Dis Model Mech, vol. 15, no. 5, May 1 2022. doi: 10.1242/dmm.049424 DOI: https://doi.org/10.1242/dmm.049424
[22] M. Lebois, M. R. Dowling, P. Gangatirkar, P. D. Hodgkin, B. T. Kile, W. S. Alexander, and E. C. Josefsson, "Regulation of platelet lifespan in the presence and absence of thrombopoietin signaling," J Thromb Haemost, vol. 14, no. 9, pp. 1882-7, Sep 2016. doi: 10.1111/jth.13397 DOI: https://doi.org/10.1111/jth.13397
[23] R. Yan, Y. Xia, K. Zhou, J. Liu, Y. Sun, C. He, X. Ge, M. Yang, C. Sun, L. Yuan, S. Li, B. Yang, F. Meng, L. Cao, C. Ruan, and K. Dai, "Essential role of glycoprotein Ibα in platelet activation," Blood Advances, vol. 8, no. 13, pp. 3388-3401, 2024/07/09/ 2024. doi: https://doi.org/10.1182/bloodadvances.2023012308 DOI: https://doi.org/10.1182/bloodadvances.2023012308
Downloads
Published
Issue
Section
License
Copyright (c) 2026 khalid Alyodawi
This work is licensed under a Creative Commons Attribution 4.0 International License.
