The regulation of muscle atrophy by enzymes of the ubiquitin-proteasome system

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Muscle wasting is a disabling response to many common conditions, including infections, cancer and diabetes, driven by a rapid increase in protein breakdown. This wasting is particularly important in lung diseases, where weakness of the chest muscles may severely affect patients‘ longterm survival. In addition, several conditions may occur simultaneously, such as steroid treatment and immobility, which further increase the severity of muscle wasting. It is established that this rapid protein breakdown is mainly caused by activation of the ‘ubiquitin system‘. Ubiquitin is a small molecule that attaches to other proteins, signalling their destruction, and recent research has shown that several enzymes of the ubiquitin system are increased in muscle wasting. The ubiquitin system is regulated by deubiquitinating enzymes (DUBs), which remove ubiquitin from proteins. So far, the precise role of DUBs in muscle breakdown remains to be determined. In this project, I will study the function of DUBs in muscle wasting, and examine how different causes of protein breakdown combine to induce severe muscle loss. In particular, I will study how DUBs affect ubiquitin levels, and measure which genes are activated in muscle breakdown. These investigations will provide essential insights into how muscle wasting is stimulated and regulated.