MITOCHONDRIA AS CAUSES OF AND THERAPEUTIC TARGETS IN CHRONIC POST-SEPSIS SKELETAL MUSCLE WEAKNESS

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was the greatest, combining functional and molecular analyses to further reveal the underlying causes. These data indicated mitochondrial abnormalities cause progressive muscle weakness after sepsis, as noted by persisting transcriptional, functional, and proteomic changes. Then I evaluated the effectiveness of the mitochondrial protecting enzyme MnSOD in preventing post-sepsis skeletal muscle weakness (Aim 2). This study examined if overexpression led to differences in skeletal muscle function following severe sepsis when compared to wildtype mice and how these functional deficits related to non-sepsis control mice. Finally, therapeutic strategies were evaluated in Aim 3. Neither providing higher oxygen concentrations during acute sepsis nor allowing for voluntary exercise after sepsis survival reduced debilitating muscle weakness. However, pharmacological treatments showed significant promise. The mitochondria-localizing tetrapeptide SS-31 provided protection against skeletal muscle weakness when administered after the development of severe sepsis. A combination of functional, histological, and biochemical techniques was utilized to provide a comprehensive overview on how mitochondrial protection prevented long-term weakness. Collectively, these studies demonstrate that mitochondrial abnormalities cause muscle weakness after sepsis. Mitochondria therefore serve as viable therapeutic targets in post-sepsis skeletal muscle weakness. Accordingly, this work suggests that mitochondria-targeting therapeutic approaches could allow sepsis survivors to recover from post-sepsis muscle weakness