Nickolai Seculov – Biomedical Science

Project Title: Signaling lipids regulate muscle metabolism after burn injury

Project Mentor: Kristin Stanford – Physiology and Cell Biology

Abstract:

Severe burn injury results in significant muscle catabolism. Muscle wasting is caused by a hypermetabolic state post-injury, characterized by catabolic processes including increased lipolysis followed by protein catabolism. Consequently, trying to mitigate muscle atrophy and its effects following burn injury may significantly improve patient outcome. Our previous studies using a rat model, have shown a loss of adipose tissue mass proceeds the loss of muscle mass. We hypothesized that the loss of adipose tissue mass altered signaling lipids which could mediate skeletal muscle metabolism.

To determine if signaling lipids were altered in response to severe burn injury, lipidomics was analyzed from plasma collected at various time points for up to 30 days from male and female human subjects who had severe burn injuries (n=7). Plasma from healthy males was used as a control. We found that a pro-inflammatory eicosanoid, 15-HETE, was upregulated on days 1and 4 after severe burn injury. This was followed by an increase in 15-oxoETE, a metabolite of 15-HETE, on day 4 and 12 after severe burn injury. Both 15-HETE and 15-oxoETE are involved in increased protein catabolism. Thus, we investigated if 15-oxoETE contributed to muscle degradation in vitro.

To further investigate this, we incubated differentiated myocytes for 4 hours with 15oxoETE, which induced the expression of genes related to protein catabolism. In an attempt to rescue the phenotype, we incubated cells with the anti-inflammatory docosanoid resolvin D1 (RvD1). RvD1 has been shown to be secreted from adipose tissue and a driver of muscle regeneration, growth, and recovery, and it was increased on days 7-25 after injury in human plasma samples We exposed myocytes to RvD1 concurrently with 15-oxoETE, and found that this blunted the effect of 15-oxoETE on muscle atrophy genes.

These data indicate 15-oxoETE as a potential contributor to muscle degradation after burn injury in humans and the involvement of RvD1 in muscle recovery after 15-oxoETE exposure. Further investigation on the effects of these lipids on muscle atrophy after severe burn injury could have significant implications on potential therapeutic treatments to delay or prevent muscle wasting following severe burn injury.