Serum activin, gene expression, muscle mass and function in people with critical illness (SAGE-MUSCLE): an observational cohort study

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Intensive Care Unit (ICU) services cost the Australian economy at least $1.1 billion annually, excluding the cost of longterm morbidity. In particular, patients with a long length of stay in ICU (> 10-14 days) consume a disproportionate amount of resources. A quarter of these patients suffer a severe weakness syndrome defined as ICU-acquired weakness (ICUAW). This catastrophic syndrome results in significant limitations to people being able to perform their usual activities required for living (e.g. standing, walking, brushing teeth, showering, toileting or feeding themselves). People who suffer ICU acquired weakness are more likely to die and experience worse physical function and quality of life up to ten years following their ICU admission. The specific cell level interactions that influence this weakness syndrome are yet to be fully understood. The protein activin limits muscle growth and causes severe muscle wasting. It has recently been shown to not only have strong regulatory effects on muscle mass in mice with cancer, and when blocked, beneficial effects such as reversal of muscle loss. It is known that blood activin levels are significantly higher in people with critical illness who have infection, however the effect this has on muscle mass and weakness has not been established in this setting. There is also emerging evidence that there may be differences in the genes that turn on and off in people within the first 5 days of an ICU stay. It is logical that genes might also turn on and off differently in people who develop severe weakness in ICU compared to those who don‘t. However no studies have looked at differences in these gene patterns and compared them with changes in weakness or the ability to breathe independently. The project will compare levels of the protein activin and gene expression patterns (i.e. differences in genes turning on and off) in people admitted to the ICU with and without severe weakness. The investigators will also test muscle strength and the ability of the patient to do functional tasks (e.g. stand up, walk) and the project aims to provide proof-of-concept of an association between protein and gene measurements with muscle strength and function in ICU patients. the results will be used to design future projects investigating i) mechanisms associated with the development of clinically significant weakness and possible therapeutic pathways and ii) prevention strategies to reduce exposure to agents associated with severe weakness in ICU.