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 (Pi) and phosphocreatine (PCr) resonances during saturation of ␥ATP 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. mitochondria ͉ mitochondrial oxidative phosphorylation ͉ muscle dysfunction ͉ nuclear magnetic resonance

Molecular research technologies in mitochondrial diseases: The microarray approach

“…These findings point to a possible role of amino acid metabolism in the pathogenesis of mitochondrial disease suggesting that: (i) the urea cycle may be crucial in disease progression, and (ii) steps in the arginine metabolic pathway are promising targets for novel therapeutic approaches. The up-regulation of many genes involved in amino acid and protein metabolism is well documented in skeletal muscle mitochondrial dysfunction after burn injury (23), further validating these findings.…”

Analysis of factorial time-course microarrays with application to a clinical study of burn injury

“…Hypermetabolism and inflammation are two hallmarks of the body's response to burn injury (15,16). Our analysis reveals that significantly enriched pathways in C1 include glycosphingolipid biosynthesis-globoseries (5 genes, p value: 8.19E-5), primary immunodeficiency signaling (10 genes, p value: 0.001), keratan sulfate biosynthesis (5 genes, p value: 0.007), galactose metabolism (5 genes, p value: 0.01), ubiquinone biosynthesis (8 genes, p value: 0.01) , death receptor signaling (7 genes, p value: 0.01), and mitochondrial dysfunction (12 genes, p value: 0.01) (the p values are calculated from the hypergeometric test; see SI Text for the details of pathway analysis).…”

“…Mitochondrial dysfunction and mitochondria related ubiquinone biosynthesis are among the top enriched pathways in both C1 and C2 groups, suggesting that mitochondrial functions are significantly affected by both burn and age. A limited number of previous animal studies have found that mitochondrial genes and function are decreased in skeletal muscle, liver, and cardiac muscle following burn injury (16). Fig.…”

Detection of the MicroRNA Expression Profile in Skeletal Muscles of Burn Trauma at the Early Stage in Rats

“…Cutaneous burn and hind limb unloading have an additive effect on muscle atrophy, characterized by loss of muscle mass and decrease in muscle strength in both fast (PL) and slow (SL) twitch muscles. [2][3][4][5] Body weight, muscle wet weight and protein weight of rats in burn group were decreased significantly compared with sham group. [6] Following a large burn, skeletal muscle plays an differentiation.…”

“…[7] Growing evidence suggests that the main mechanisms underlying skeletal muscle wasting induced by severe burn include activation of ubiquitin-proteasome pathway, [8][9][10] myonuclear apoptosis, [1] mitochondrial dysfunction, [5,7] autophagy [1] signaling pathways driving muscle inflammation, and protein metabolism. [11] MicroRNAs (miRNAs) belong to a group of noncoding small RNAs with a length of 20-24 ribonucleotides, which play a critical role in post-transcriptional regulation of gene expression.…”