Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness

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Project Summary Survival of critical illness such as sepsis and acute respiratory failure is accompanied by serious physical complications with many patients acquiring long-term impairments. Mechanisms and factors that impede the recovery of muscle size and function after hospitalization are not understood. It is unclear if recovery after critical illness leads to a subsequent deficiency in the ability to make new proteins (protein synthesis) or if a catabolic/inflammatory environment persists preventing muscle regrowth which involves muscle stem cell (satellite cell) fusion to myofibers. We will address gaps in knowledge by studying skeletal muscle proteostasis, cellular environment, and RNA and mitochondrial biogenesis after critical illness with closely aligned physical function outcomes. Understanding the cellular environment in the period after hospital release, and how it impacts muscle protein turnover will direct efforts to effective therapies to accelerate muscle regrowth. The overall goal of this application is to identify cellular properties of muscle that may contribute to long-term physical disability in survivors of critical illness. Overall, I hypothesize that aberrant cellular processes in muscle are underlying prolonged functional impairments in patients after critical illness. In Aim 1, we will determine the longitudinal trajectory of muscle and physical function recovery and establish muscle morphological and cellular characteristics in patients after critical illness. We hypothesize that patients with higher severity of illness in the ICU and with longer duration of mechanical ventilation will have the most persistent muscle weakness and deficits in muscle power in recovery. In Aim 2, we will identify cellular mechanisms that contribute to muscle dysfunction after critical illness. We hypothesize that patients with persistent muscle weakness and fatigue have impaired mitochondrial function compared to controls. Moreover, we hypothesize that survivors of critical illness have elevated myofibrillar protein synthesis and ribosome biogenesis in early recovery, but muscle regrowth does not occur due to elevated proteolysis. The overarching goal of this proposal focuses on elucidating the factors that lead to muscle mass dysregulation in recovery and inform why some patients develop persistent disability and others gradually improve. The proposed mentoring team provides the knowledge and training to develop into an independent clinical investigator integrating basic and applied science. The proposed training plan in Aim 1 emphasizes clinical trial methodologies and complex longitudinal analyses. For aim 2, the training focuses on skeletal muscle experiments; specifically, knowledge to assess muscle proteostasis, mitochondrial content and function, and muscle morphology. I will learn the technical skills to examine skeletal muscle including stable isotope labeling, immunohistochemistry, western blot analysis, and microscopy will be gained. Moreover, the proposed research and training plan provides the necessary training and mentorship to translate findings in this proposal into the development of targeted rehabilitation and pharmacological interventions in future R01 studies.