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Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling

Alyodawi, Khalid; Vermeij, Wilbert; Omairi, Saleh; Kretz, Oliver; Hopkinson, Mark; Solagna, Francesca; Joch, Barbara; Brandt, Renata; Barnhoorn, Sandra; Van Vliet, Nocole; Ridwan, Yanto; Essers, Joroen; Mitchell, Robert; Morash, Taryn; Pasternack, Arja; Ritvos, Olli; Matsakas, Antonios; Collins-Hooper, Henry; Huber, Tobias; Hoeijmakers, Jan; Patel, Ketan

Authors

Khalid Alyodawi

Wilbert Vermeij

Saleh Omairi

Oliver Kretz

Mark Hopkinson

Francesca Solagna

Barbara Joch

Renata Brandt

Sandra Barnhoorn

Nocole Van Vliet

Yanto Ridwan

Joroen Essers

Robert Mitchell

Taryn Morash

Arja Pasternack

Olli Ritvos

Henry Collins-Hooper

Tobias Huber

Jan Hoeijmakers

Ketan Patel



Abstract

© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders Background: One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit. Methods: To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone. Results: We show that muscle of Ercc1Δ/− progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40–60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30–62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6m in untreated mice vs. 13.7m in treated) and increased specific force (19.3mN/mg in untreated vs. 24.0mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30mm3 in treated progeroid mice vs. 0.14mm3 in untreated mice, cortical bone volume; 0.30mm3 in treated progeroid mice vs. 0.22mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5weeks) and their severity reduced, overall sustaining health without affecting lifespan. Conclusions: This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.

Citation

Alyodawi, K., Vermeij, W., Omairi, S., Kretz, O., Hopkinson, M., Solagna, F., …Patel, K. (2019). Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling. Journal of Cachexia, Sarcopenia and Muscle, 10(3), 662-686. https://doi.org/10.1002/jcsm.12404

Journal Article Type Article
Acceptance Date Jan 9, 2019
Online Publication Date Mar 27, 2019
Publication Date Jun 1, 2019
Deposit Date Feb 20, 2019
Publicly Available Date Mar 29, 2024
Journal Journal of Cachexia, Sarcopenia and Muscle
Print ISSN 2190-5991
Electronic ISSN 2190-6009
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 10
Issue 3
Pages 662-686
DOI https://doi.org/10.1002/jcsm.12404
Keywords Compression; Morbidity; Progeroid; Ageing; Skeletal muscle; Myostatin; Liver; Kidney; Bone; Neurological
Public URL https://hull-repository.worktribe.com/output/1210980
Publisher URL https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12404

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Copyright Statement
© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.





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