Skeletal muscle is a highly plastic tissue capable of spontaneous repair in response to injury via the recruitment of muscle stem cells called the satellite cells. These cells are localised within the myofibre basal lamina and are activated upon muscle damage, they proliferate and differentiate to replace the damaged muscle. Satellite cells are the key rate-limiting step for successful repair and the transcriptional cues that emanate from the skeletal muscle to activate regeneration are unclear. Thus, discovery of key molecules that regulate satellite cell activation will accelerate the ability to stimulate muscle repair. Estrogen related receptors (ERR isoforms 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. Skeletal muscle-specific overexpression of ERRγ has been shown to drive metabolic and angiogenic muscle reprogramming in both health and disease. This project will test the hypothesis that targeting ERRγ in skeletal muscle will improve the myofibre regenerative capacity via satellite cell recruitment and secretion of growth factors. Identification of the underlying mechanisms will provide new knowledge that can be exploited to develop new therapeutic avenues for promoting satellite cell recruitment and myofibre regeneration in terms of injury or degenerative conditions like ageing and muscle wasting disorders. The hypothesis will be tested by addressing the following specific aims: 1) To establish the satellite cell proliferation and differentiation profiles in ERRγ transgenic muscles at baseline and in response to acute eccentric exercise. 2) To investigate the effect of ERRγ on satellite cell recruitment in response to muscle injury. 3) To determine the interplay between muscular revascularisation and reparative myogenesis by ERRγ. 4) To determine whether an AAV-mediated ERRγ delivery increases satellite cell recruitment and improves muscle integrity.
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