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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; 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

Authors

Khalid Alyodawi

Wilbert Vermeij

Saleh Omairi

Oliver Kretz

Francesca Solagna

Barbara Joch

Renata Brandt

Sandra Barnhoorn

Nocole Van Vliet

Yanto Ridwan

Joroen Essers

Robert Mitchell

Taryn Morash

Arja Pasternack

Olli Ritvos

Antonios Matsakas

Henry Collins-Hooper

Tobias Huber

Jan Hoeijmakers



Abstract

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: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/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 72 h 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 177 nm 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; 0.30 mm3 in treated progeroid mice vs. 0.14 mm3 in untreated mice, cortical bone volume; 0.30 mm3 in treated progeroid mice vs. 0.22 mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) 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.

Journal Article Type Article
Publication Date 2019-06
Print ISSN 2190-5991
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 10
Issue 3
Pages 662-686
APA6 Citation Alyodawi, K., Vermeij, W., Omairi, S., Kretz, O., Solagna, F., Joch, B., …Hoeijmakers, J. (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
DOI https://doi.org/10.1002/jcsm.12404
Keywords Compression, morbidity
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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