Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling
2019
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
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