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

Project Summary The number of patients surviving critical illnesses in the United States continues to rise each year. Survival, however, is not without serious long-term physical complications with many patients acquiring crippling disability. Patients who have survived critical illness have arduous recoveries that are plagued by an inability to regrow muscle tissue after hospital discharge. The inability to grow muscle after hospital discharge reduces the likelihood of patients returning to their pre-hospital functional level and increases the risk of secondary complications such as readmission and death. Clinical and muscle cellular factors driving skeletal muscle dysfunction are relatively unknown after an acute critical illness. We will address this knowledge gap by studying skeletal muscle protein turnover, cellular signaling pathways, and RNA and mitochondrial biogenesis early after critical illness and correlate these muscle cellular factors with functional outcomes. The overall goal of the study is therefore to determine factors associated with the underlying failure to recover muscle and understand the relationship with physical function in survivors of critical illness. In Aim 1, we will examine the trajectory of muscle and physical function recovery after critical illness and to determine whether morphological and cellular characteristics associate with sustained disability. We hypothesize that patients with higher index severity of illness with longer duration of mechanical ventilation will have muscle weakness and minimal to no muscle regrowth 6-months after discharge. In aim 2, we will determine the cellular mechanisms that lead to muscle dysfunction after critical illness. We have two primary hypotheses: 1) patients surviving critical illness that have persistent muscle weakness and fatigue have impaired mitochondrial respiration with reduced mitochondrial protein synthesis; and 2) 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 the early phase of 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 emphasizes skeletal muscle experiments at the cellular level; specifically, technical skills and knowledge to assess muscle protein synthesis and degradation through stable isotope labeling, immunohistochemistry, western blot analysis, and microscopy will be gained. Moreover, the proposed research provides the necessary training and mentorship on clinical trials methodologies and execution, statistical analyses, and dissemination. The findings of this study will determine which cellular properties of skeletal muscle and clinical factors after critical illness are related to physical function, which will inform the development of targeted rehabilitation interventions in future R01 studies.