The Role of Mitochondrial Biogenesis in Muscle Function recovery in Critical Illness

Infection can trigger an exaggerated host response by the body (‘sepsis‘) that can lead to failure of multiple organs and a requirement for prolonged life support in the intensive care unit (ICU). Sepsis is a major worldwide cause of death while survivors often suffer long-term disability, notably muscle weakness. Dysfunction of mitochondria, the energy powerhouses that fuel the cell‘s metabolism, appears to be an important mechanism underlying multi-organ failure. The degree of mitochondrial dysfunction relates to poor outcomes in ICU patients. Notably, biological triggers stimulating production of new mitochondria (‘biogenesis‘) are increased at an early stage in survivors but not in those who eventually die. I therefore wish to explore the relationship between mitochondrial biogenesis and restoration of muscle function in the recovery phase following sepsis in both an animal model and in ICU patients. In the model I propose to also use agents that both activate and inhibit mitochondrial biogenesis to see whether restoration of muscle function is directly affected. In patients recovering from critical illness I will assess whether graded exercise, a stimulator of biogenesis, has a positive effect on mitochondrial capacity and muscle function. If demonstrated, this may offer a new treatment target in clinical practice.

Sepsis-induced myopathy and muscle wasting is increasingly recognised as a significant contributor to poor health outcomes from critical illness. A potential mechanism may be insufficient or delayed recovery of mitochondrial (bioenergetic) function. The host lab has shown that bioenergetic failure is associated with poor outcomes in both patients and animals with severe sepsis. They have also shown that early upregulation of markers of mitochondrial biogenesis (production of new mitochondrial protein) is associated with survival in critically ill humans.

I propose to test the hypothesis that stimulation of mitochondrial biogenesis improves functional recovery of skeletal muscle on recovery from sepsis. I aim to characterise the recovery phase of a long-term rat model of faecal peritonitis with respect to restoration of bioenergetic capacity and associated improvements in skeletal muscle structure and function. In the same model, I will then either stimulate (with leptin and rosiglitazone) or inhibit (with chloramphenicol) mitochondrial biogenesis to demonstrate any influence on exercise capacity, histological recovery, and force generation using nerve stimulation.

I will complement these lab studies with a patient study where critically ill patients being weaned from mechanical ventilation will be randomised to a graded exercise regimen (as exercise is known to stimulate biogenesis) or standard rehabilitation. Muscle biopsies will be taken on day 1 after intubation and subsequently on day 7 and, if indicated, Day 21. Markers of biogenesis will be measured and compared with functional and histological recovery.

This study will hopefully demonstrate the importance of mitochondrial biogenesis on functional recovery after severe sepsis. If so, it may lead to a important new treatment paradigm that will facilitate and enhance outcomes in the critically ill patient.