Universität zu Köln

Alyodawi, Khalid, Vermeij, Wilbert P., Omairi, Saleh ORCID: 0000-0001-9169-3743, Kretz, Oliver, Hopkinson, Mark ORCID: 0000-0002-9508-8652, Solagna, Francesca, Joch, Barbara, Brandt, Renata M. C., Barnhoorn, Sander, van Vliet, Nicole, Ridwan, Yanto, Essers, Jeroen, Mitchell, Robert, Morash, Taryn, Pasternack, Arja ORCID: 0000-0002-6088-4245, Ritvos, Olli ORCID: 0000-0001-7017-6931, Matsakas, Antonios, Collins-Hooper, Henry, Huber, Tobias B. ORCID: 0000-0001-7175-5062, Hoeijmakers, Jan H. J. and Patel, Ketan (2019). Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling. J. Cachexia Sarcopenia Muscle, 10 (3). S. 662 - 687. HOBOKEN: WILEY. ISSN 2190-6009

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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 Ercc1(Delta/-) 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 mm(3) in treated progeroid mice vs. 0.14 mm(3) in untreated mice, cortical bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.22 mm(3) in untreated mice). The onset of neurological abnormalities was delayed (by similar to 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Alyodawi, Khalid UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeij, Wilbert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Omairi, Saleh UNSPECIFIED orcid.org/0000-0001-9169-3743 UNSPECIFIED Kretz, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Hopkinson, Mark UNSPECIFIED orcid.org/0000-0002-9508-8652 UNSPECIFIED Solagna, Francesca UNSPECIFIED UNSPECIFIED UNSPECIFIED Joch, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandt, Renata M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barnhoorn, Sander UNSPECIFIED UNSPECIFIED UNSPECIFIED van Vliet, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Ridwan, Yanto UNSPECIFIED UNSPECIFIED UNSPECIFIED Essers, Jeroen UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitchell, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Morash, Taryn UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasternack, Arja UNSPECIFIED orcid.org/0000-0002-6088-4245 UNSPECIFIED Ritvos, Olli UNSPECIFIED orcid.org/0000-0001-7017-6931 UNSPECIFIED Matsakas, Antonios UNSPECIFIED UNSPECIFIED UNSPECIFIED Collins-Hooper, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Huber, Tobias B. UNSPECIFIED orcid.org/0000-0001-7175-5062 UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Patel, Ketan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-146181
DOI:	10.1002/jcsm.12404
Journal or Publication Title:	J. Cachexia Sarcopenia Muscle
Volume:	10
Number:	3
Page Range:	S. 662 - 687
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2190-6009
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SKELETAL-MUSCLE; LIFE-SPAN; DNA-REPAIR; NUCLEAR ABNORMALITIES; MOLECULAR-MECHANISMS; CELL-PROLIFERATION; SATELLITE-CELL; GROWTH; MASS; HYPERTROPHY Multiple languages Geriatrics & Gerontology; Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14618