The Role of Mitochondrial Dysfunction in Physical Recovery after Critical Illness
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PROJECT SUMMARY Each year, over 100,000 Veterans survive an intensive care unit (ICU) stay for critical illness, but up to half develop devastating and persistent impairments in physical function. Rehabilitation studies have demonstrated limited efficacy to date, and little is known about the mechanistic underpinnings that link critical illness and persistent physical function impairment. Improved understanding of underlying mechanisms is urgently needed to improve long-term outcomes and allow for the development of effective interventions. During critical illness due, patients suffer from profound impairments in energy generation in skeletal muscle due to disruptions in oxidative phosphorylation that leads globally reduced mitochondrial oxidative capacity. Whether mitochondrial oxidative capacity normalizes in survivors, however, is unknown. Our preliminary data indicates that ICU survivors suffer from impaired mitochondrial oxidative capacity as a form of bioenergetic failure that limits physical recovery months after hospitalization. The hypothesis for this career development proposal is that reduced mitochondrial oxidative capacity in survivors of critical illness is associated with worse physical function. To test this hypothesis, we will conduct the “Altered energy Metabolism and PhysicaL Function in recoverY after the ICU” (AMPLiFY-ICU) prospective, observational cohort study. We will enroll 62 Veterans who have survived critical illness and measure mitochondrial oxidative capacity using skeletal muscle 31P-magnetic resonance spectroscopy (31P-MRS) and peripheral blood mononuclear cell oxygen consumption via extracellular flux analysis at 3 months post- discharge and determine their association with physical function at 6-month follow-up. Aim 1 will test the hypothesis that reduced muscle-specific mitochondrial oxidative capacity, measured using 31P-MRS 3 months post discharge is associated with worse physical function (measured by the primary outcome of six-minute walk distance, 6MWD) at 6-month follow-up. Aim 2 will test the hypothesis that reduced systemic mitochondrial oxidative capacity measured in peripheral blood mononuclear cells (PMBCs) at 3 months post-discharge is associated with reduced physical function at 6-month follow-up. Aim 3 will explore whether reduced mobility in the ICU is associated with reduced mitochondrial oxidative capacity (31P-MRS & PBMCs) at 3-month follow-up. The goal of the study outlined in this proposal is characterize the role of mitochondrial capacity on long- term physical function after critical illness and its association with ICU mobility. This work will advance the field by utilizing novel research approaches to characterize understudied mechanisms of physical recovery and provide a foundation for physiologically targeted interventions. This proposal will also foster Dr. Mart’s scientific career development by providing him the training, mentorship, and resources necessary to pursue a career merging the insights of applied exercise physiology, critical care medicine, and functional outcomes to develop novel therapeutic interventions. Through this award, Dr. Mart will accomplish his career development and training objectives to develop unique expertise in: (1) longitudinal critical care studies and clinical trials, (2) approaches to measuring physical function, (3) translational methods in applied exercise physiology research, and (4) effective scientific and grant writing. In completing the proposed study and career development plan, Dr. Mart will mature into a national leader on physical outcomes after critical illness with the skillset to develop new interventions aimed at helping patients restore their function and quality of life.
