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

Alyodawi, K., Vermeij, W. P., Omairi, S., kretz, O., Hopkinson, M., Solagna, F., Joch, B., Brandt, R. M. C., Barnhoorn, S., van Vliet, N., Ridwan, Y., Essers, J., Mitchell, R., Morash, T., Pasternack, A., Ritvos, O., Matsakas, A., Collins-Hooper, H., Huber, T. B., Hoeijmakers, J. H. J. and 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). pp. 662-686. ISSN 2190-6009

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To link to this item DOI: 10.1002/jcsm.12404

Abstract/Summary

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 hindlimb muscle mass of 40-60% compared to normal mass) which is largely protected by attenuating Myostatin/Activin signalling using sActRIIB (increase of 30-62% compared to untreated progeric). sActRIIB treated progeroid mice maintained muscle activity (distance travel per hour 5.6m in untreated mice versus 13.7m in treated) and increased specific force (19.3mN/mg in untreated versus 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 versus 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 versus 15.7 in untreated) which is likely to be a result in the normalisation of podocyte foot processes which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224nm 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 versus 8.1% treated) and osteoporosis (trabecular bone volume; 0.30mm3 in treated progeroid mice versus 0.14mm3 in untreated mice, cortical bone volume; 0.30mm3 in treated progeroid mice versus 0.22mm3 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

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:81545
Publisher:Wiley

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