Grant: Project Grant

Intensive care unit-acquired weakness (ICUAW) describes muscle weakness that develops in some people who have been admitted to an ICU with a serious illness. It is associated with problems such as prolonged ICU length of stay, and increased ICU, hospital, and 1-year rates of death. In up to 50% of critical illness survivors, muscle wasting and weakness lasts a lifetime and cause permanent physical disability, reduced quality of life, inability to work, and increased number of return trips to hospital. This also negatively impacts the individual's caregivers, who demonstrate increased incidence of depression. We have no therapy that is capable of preventing, or treating, ICUAW sustained months after ICU discharge because we do not understand the mechanisms that cause persistent wasting and weakness in the critical illness survivor. Our group has shown that the ability of muscle to re-grow following wasting in the ICU is permanently impaired in patients who have sustained ICUAW. We found that muscle stem (satellite) cells are lost, implying the muscle is unable to regenerate. We have identified some molecular regulators, known as microRNAs (miRs), are likely to play a causative role. In this study we propose to determine the mechanism by which our candidate factors impair muscle regeneration and growth and determine if we can in turn, impact muscle regeneration and growth by modulating our candidate factors in cell culture models and patients with ICUAW. The significance and strength of this proposal lies in its potential translatability to the clinical setting. By generating totally novel insights into sustained muscle wasting and potential therapeutic target identification, this will allow us to develop various approaches aimed at limiting loss of, and/or enhancing growth of muscle in individuals with sustained ICUAW.