Reduced rate of adenosine triphosphate synthesis by in vivo 31P nuclear magnetic resonance spectroscopy and downregulation of PGC-1β in distal skeletal muscle following burn

Abstract

Abstract. Using a mouse model of burn trauma, we tested the hypothesis that severe burn trauma corresponding to 30% of total body surface area (TBSA) causes reduction in adenosine triphosphate (ATP) synthesis in distal skeletal muscle. We employed in vivo 31 P nuclear magnetic resonance (NMR) in intact mice to assess the rate of ATP synthesis, and characterized the concomitant gene expression patterns in skeletal muscle in burned (30% TBSA) versus control mice. Our NMR results showed a significantly reduced rate of ATP synthesis and were complemented by genomic results showing downregulation of the ATP synthase mitochondrial F 1 F 0 complex and PGC-1ß gene expression. Our findings suggest that inflammation and muscle atrophy in burns are due to a reduced ATP synthesis rate that may be regulated upstream by PGC-1ß. These findings implicate mitochondrial dysfunction in distal skeletal muscle following burn injury. That PGC-1ß is a highly inducible factor in most tissues and responds to common calcium and cyclic adenosine monophosphate (cAMP) signaling pathways strongly suggests that it may be possible to develop drugs that can induce PGC-1ß.

Burn trauma in skeletal muscle results in oxidative stress as assessed by in vivo electron paramagnetic resonance

“…The principal findings of the present study are complementary to findings by NMR, suggesting that a major factor in the progression of mitochondrial skeletal muscle dysfunction in burns results from defects in oxidative phosphorylation (OXPHOS) (22)(23)(24)33,34). Indeed, findings with the same mouse 'local' burn model (affecting the hind limb and representing 3-5% of total body surface area) demonstrated that burn injury causes a significant dysregulation in OXPHOS and a decrease in the ATP synthesis rate (23).…”

“…We also propose that it is complementary to NMR, which has already shown the consequences of bioenergetic and mitochondrial dysfunction in vivo (22)(23)(24)(25). Thus, our results lead us to conclude that bioenergetic dysfunction and insufficient oxidative defense following local burn trauma may lead to oxidative damage.…”

“…Hence, inhibition of OXPHOS is predicted to result in the progressive destruction of mtDNA. Since OXPHOS is significantly inhibited in skeletal muscle post burn (23,24), we hypothesized that the mitochondria should produce higher levels of ROS post burn. This has been confirmed in this study.…”

“…NMR is a useful method for measuring biomarkers in vivo, and has already shown relevance in the study of the metabolism and bioenergetics of skeletal muscle (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In addition to NMR spectroscopy, the development of highthroughput microarray systems, capable of simultaneously measuring the expression of thousands of genes, has also greatly advanced our ability to detect and measure biomarkers.…”

Microarray analysis suggests that burn injury results in mitochondial dysfunction in human skeletal muscle

“…A recent study reported downregulation of the PPARγ coactivator 1ß (PGC-1ß) in a murine burn model (8), suggesting a novel mode of regulation for numerous complex biological programs, including metabolism by coactivator proteins (9,10). The first member of the PGC-1 family, PGC-1α, was identified from brown adipose tissue as a PPARγ-interacting protein (11).…”