Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - MUSTEMERR (Regulation of muscle stem cells by ERRgamma)

1. Publishable summary
Skeletal muscle stem cells called the satellite cells are localized within the myofibre basal lamina and are activated upon muscle injury, they then proliferate and differentiate to replace the damaged muscle. Satellite cells play a crucial role in maintaining skeletal muscle homeostasis and repair and are the key rate-limiting step for successful regeneration. Recent evidence has improved our understanding of the mechanisms underlying skeletal muscle metabolic reprogramming and its ability regenerate after damage. In particular, Estrogen Related Receptors (ERR α, β and γ) are a sub-family of orphan nuclear hormone receptors that have been identified as major regulators of cellular and mitochondrial metabolism. In 2012/13 the fellow reported that skeletal muscle-specific over-expression of ERRγ drives metabolic and angiogenic muscle reprogramming that was beneficial in both health and disease. The MUSTEMERR project tests the hypothesis that targeting ERRγ in skeletal muscle will improve the myofibre regenerative capacity via satellite cell recruitment and growth factor secretion. ERRγ–driven metabolic and angiogenic myofibre remodelling will be protective to muscle subjected to stimuli that cause damage and are followed by regeneration. The project is focused on the following main objectives: (1) Establish the satellite cell proliferation and differentiation profiles in ERRγ transgenic muscles at baseline and in response to acute eccentric exercise. (2) Investigate the effect of ERRγ on satellite cell recruitment in response to muscle injury. (3) Determine the interplay between muscular revascularisation and reparative myogenesis by ERRγ. (4) Determine whether an AAV-mediated ERRγ delivery increases satellite cell recruitment and improves muscle integrity and function. In the past two years we have made great progress towards the completion of objectives (1) and (2) and some effort has taken place addressing objective (3). During the project the fellow has found that ERRγ transgenesis does not result in an increase in skeletal muscle satellite cells. To our surprise the satellite cell pool of this mouse model is significantly lower compared to wild type mice. When this mouse is crossed with the hyper-muscular myostatin null mouse -that is known to have a satellite cell deficit-, the satellite cell number is further reduced and a large number of fibres has a single satellite cell. Fibre cultures revealed lower cells per cluster and fewer clusters compared to control despite a proportional increase in satellite cell progeny. Remarkably, when challenged with injury, ERRγ overexpression in myostatin deficient mice leads to accelerated muscle regeneration highlighting the importance of microcirculation during regeneration. Since the initiation of the grant, the fellow has been appointed as a lecturer in Biomedical Sciences at the Hull York Medical School, University of Hull. He made substantial progress in his career goals by creating his own research group composed currently of 3 fully funded PhD students, 1 MSc student supported by the Wolfson Foundation and his group is supported by 1 technician. He also co-supervises 2 PhD students from other laboratories. Since 2014 he has published 4 articles, one of which contains findings of the MUSTEMERR project (i.e. Matsakas et al. Elife. 2016 Aug 5;5. pii: e16940).

Contact

Phil MacDonald, (Director of Finance)
Tel.: +441482465266
E-mail

Subjects

Life Sciences
Record Number: 192232 / Last updated on: 2016-12-15
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