Burn injury causes mitochondrial dysfunction in skeletal muscle

Abstract

Severe burn trauma is generally followed by a catabolic response that leads to muscle wasting and weakness affecting skeletal musculature. Here, we perform whole-genome expression and in vivo NMR spectroscopy studies to define respectively the full set of burn-induced changes in skeletal muscle gene expression and the role of mitochondria in the altered energy expenditure exhibited by burn patients. Our results show 1,136 genes differentially expressed in a mouse hind limb burn model and identify expression pattern changes of genes involved in muscle development, protein degradation and biosynthesis, inflammation, and mitochondrial energy and metabolism. To assess further the role of mitochondria in burn injury, we performed in vivo (31)P NMR spectroscopy on hind limb skeletal muscle, to noninvasively measure high-energy phosphates and the effect of magnetization transfer on inorganic phosphate (P(i)) and phosphocreatine (PCr) resonances during saturation of gammaATP resonance, mediated by the ATP synthesis reactions. Although local burn injury does not alter high-energy phosphates or pH, apart from PCr reduction, it does significantly reduce the rate of ATP synthesis, to further implicate a role for mitochondria in burn trauma. These results, in conjunction with our genomic results showing down-regulation of mitochondrial oxidative phosphorylation and related functions, strongly suggest alterations in mitochondrial-directed energy expenditure reactions, advancing our understanding of skeletal muscle dysfunction suffered by burn injury patients.

Fig. 1.

Several differentially expressed genes for hind limb burn belong to one of four functional categories, as identified by using Gene Ontology and KEGG metabolic pathways at P ≤ 0.05. Black bars indicate number of up-regulated genes; gray bars correspond to down-regulated genes in the hind limb burn model versus control mice (left y axis). The negative log10 of P values represented by asterisks are indicated in the right y axis.

Fig. 2.

Differentially expressed genes at three time points after hind limb burn. Group A includes genes involved in carbohydrate metabolism, group B represents fatty acid metabolism genes, and group C includes genes involved in oxidative metabolism. Red boxes represent up-regulation of the gene, and blue boxes represent down-regulation of the gene compared with normal unburned muscle.

Fig. 3.

NMR spectra of in vivo ³¹P NMR saturation-transfer performed on the hind limb skeletal muscle of awake mice. Representative summed ³¹P-NMR spectra acquired from normal and burned mice before (A) and after (B) saturation of the γATP resonance, with the difference spectrum between the two (A–B). The arrow indicates the position of the saturation (sat) by rf irradiation (-2.4 ppm). Pi, inorganic phosphate; ppm, chemical shift in parts per million.