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

Abstract

Burn injuries to extensive areas of the body are complicated by muscle catabolism. Elucidating the molecular mechanisms that mediate this catabolism may facilitate the development of a medical intervention. Here, we assessed the functional classification of genes that were differentially expressed in skeletal muscle following burn injury in 19 children (5.2+/-4.0 years of age), (64+/-15% total burn surface area, TBSA) relative to 13 healthy controls (11.9+/-6.0 years of age). Microarray analysis of samples taken within 10 days of burn injury revealed altered expression of a variety of genes, including some involved in cell and organelle organization and biogenesis, stress response, wound response, external stimulus response, regulation of apoptosis and intracellular signaling. The genes that encode peroxisome proliferator-activated receptors (PPARs; 3 isotypes PPARalpha, PPARgamma and PPARdelta also known as PPARbeta or PPARbeta/delta), which may serve as transcriptional nodal points and therapeutic targets for metabolic syndromes, were among those affected. In particular, expression of the main mitochondrial biogenesis factor PPARgamma-1beta (or PGC-1beta) was downregulated (P<0.0001), while the expression of PPARdelta was upregulated (P<0.001). Expression of PGC-1alpha, the closest homolog of PGC-1beta was upregulated (P=0.0037), and expression of the gene encoding mitochodrial uncoupling protein 2 (UCP2) was also upregulated (P=0.008). These results suggest that altered PPAR and mitochondrial gene expression soon after burn injury may lead to metabolic and mitochondrial dysfunction in human skeletal muscle.

Figure 1

Functional classification of differentially downregulated genes in skeletal muscle biopsies of 19 burned children relative to those of 13 healthy control subjects. Genes showing significant differential expression (cutoff of 5% false discovery rate and 1.4-fold change) were grouped based on Gene Ontology functional classification. Bars indicate the number of downregulated genes (*P<0.05; **P<0.01).

Figure 2

PGC-1ß and PGC-1α gene mRNA expression in muscle tissue from patients who suffered 30% TBSA burns. Gray columns represent gene expression from 19 burned children and white columns represent gene expression from 13 control subjects. PGC-1ß expression was significantly downregulated at early time points post-burn. There was a concurrent compensatory increase in PGC-1α expression. (^*t-test, 2-tailed, equal variances).

Figure 3

PPARα, PPARδ and UCP2 transcription in tissue from burn patients. Gray columns represent gene expression from 19 burned children and white columns represent gene expression from 13 control subjects. PGC-1α·expression was significantly downregulated at early time points post-burn. There was a concurrent significant compensatory increase in PGC-1δ expression. The expression of UCP2 was also significantly increased. (^*t-test, 2-tailed, unequal variances).