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Title: Attenuation of myostatin/activin signalling delays skeletal muscle ageing signs in a progeric mouse model
Author: Alyodawi, Khalid
ISNI:       0000 0004 7971 9367
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2019
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Accumulation of DNA damage with age induces a stress response that shifts cellular resources from growth towards maintenance. A mouse model with defectsin DNA damage repair, Ercc1Δ/- , has noticeable growth retardation and multisystemic ageing signs. Skeletal muscle wasting, locomotor activity and reduce muscle strength are the most apparentsigns of accelerated ageing in this model. Using anti myostatin as a strategy in health and disease condition offer a unique approach to increase muscle mass or prevent muscle loss. However, it might be a conflict with the output of stress response in the aged and progeric muscle. The hypothesis that we tested here is the maintenance of skeletal muscle growth through attenuation of myostatin/activin signalling in progeric Ercc1Δ/- mice could counteract the effect of DNA damage and stress response and delay signs of ageing. Eight weeks old male mice FVB/C57/Bl6, before the development of progeric features were injected intraperitoneally with sActRIIB. Animal weights were measured weekly. Life was even terminated at 16 weeks before the onset of premature death or animals leaves until the end of life in life span cohort. As a result of myostatin (Mstn) antagonism, there was an increase in body mass in Ercc1 Δ/- and Ercc1+/+ mice. All muscles were heavier in treated progeric and control mice. Muscle mass increase due to increase in CSA of all types of fibres. Antagonism of Mstn attenuates the decline in locomotor activity and muscle strength in progeric mice. However, there was a reduction in activity and strength in control treated mice. Antagonism of Mstn attenuates fibre damage and promotes fibre survival in progeric mice. Supra-normalisation of mechanical force transduction apparatus of progeric muscle by sActRIIB. Partial normalisation of progeric muscle stem cells by sActRIIB was noted. The main findings of this study are the Ercc1Δ/- progeric mouse model shows many features of naturally aged mice in term of sarcopenia. These characteristics were attenuated through the antagonism of Myostatin/Activin signalling, even with a persistent defect in DNA damage repair system. The enhancements were at the level of locomotor activity, muscle strength and delayed parameters of neurodegeneration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral