Muscle and physical function recovery after acute critical illness

Many patients who survive critical illness, including sepsis and acute respiratory failure, have arduous recoveries plagued by an inability to recover muscle and physical function after hospital discharge, resulting in lower quality of life, inability to return to work and disability. The number of patients surviving critical illnesses in the United States continues to rise each year and therefore it is critically important to develop interventions that will support their recovery. Clinical and muscle cellular factors driving skeletal muscle dysfunction are relatively unknown after an acute critical illness, but are necessary to inform intervention development. We will address this knowledge gap by studying myofibrillar and collagen protein turnover, cellular signaling pathways, and markers of damage, inflammation and immune response in the first year of recovery. The unique aspect of this proposal is the serial, intra-patient muscle tissue sampling paired with simultaneously obtained clinical functional parameters over the first year of recovery post hospital discharge. Physical function and quality of life outcomes will be assessed to understand why some patients recover muscle function, yet others develop severe disability. The overall goal of this clinical observational study is to elucidate the cellular environment and the patient's clinical characteristics contributing to failed muscle recovery and physical disability in survivors of critical illness. Our central hypothesis is that alterations in myofibrillar, mitochondrial and collagen protein homeostasis are underlying muscle and physical dysfunction in patients surviving critical illness. In Aim 1, we will identify trajectory of recovery for muscle strength and power, as well as physical function in patients surviving ICU-related critical illness including pneumonia, sepsis, and COVID-19 etiologies. We hypothesize that patients with a higher initial severity of illness will show poor recovery of muscle strength and physical function during the first year of recovery. In Aim 2, we will determine mechanisms of skeletal muscle deficiencies contributing to disparate recovery in patients surviving ICU-related COVID-19 or other acute lung injury etiologies. We hypothesize that patients with longer ICU durations will show poor recovery of muscle size and increased collagen deposition during the first year of recovery. In addition, we hypothesize that patients with persistent weakness and fatigue have prolonged impairments in mitochondrial function compared to patients who recover their muscle function. Finally, we hypothesize that patients with long-term disability have an inability to recover muscle function due to a cellular environment of that is not permissive to a positive protein balance. We will use stable isotope mass spectroscopy measurements of muscle biopsies to determine synthesis of myofibrillar, mitochondrial and collagen protein. Findings from this study, will inform why some patients develop persistent disability and others gradually improve. The results from this research will guide future development of therapeutic interventions that are specific to skeletal muscle deficits with consideration for patient related factors such as age and co-morbid burden.