Gene expression profiles and protein balance in skeletal muscle of burned children after β-adrenergic blockade

Abstract

Propranolol, a nonselective β-blocker, has been shown effective in hypermetabolic burn patients by decreasing cardiac work, protein catabolism, and lipolysis. This study investigates the effect of propranolol on gene and protein expression changes in skeletal muscle of burned children by use of high-density oligonucleotide arrays to establish the genetic profiles and stable isotope technique to quantitate protein synthesis. Thirty-seven children (mean age 9.7 ± 1.1 yr) were randomized into groups to receive placebo ( n = 23) or propranolol ( n = 14) titrated to reduce heart rate by 15%. Children had >40% total body surface area burns (mean 43 ± 5.6%). Protein net balance was determined by stable-isotope infusion technique. Total RNA from muscle biopsies was isolated, labeled, and cRNA hybridized to the HG-U95Av2 Affymetrix array. Mean net balance of protein synthesis and breakdown was –14.3 ± 12.9 nmol · min–1 · 100 ml leg volume–1 for placebo and +69.3 ± 34.9 nmol · min–1 · 100 ml leg volume–1 in the propranolol-treated children ( P = 0.012). Comparison of 12,000 genes in burned children receiving placebo showed increased expression of two genes with time, whereas children receiving propranolol showed increased expression of nine genes with a decrease in five genes. We conclude that burned children receiving propranolol showed a significant upregulation in genes involved in muscle metabolism and downregulation of an important enzyme involved in gluconeogenesis and insulin resistance compared with burned children receiving placebo. The upregulation of genes involved in muscle metabolism correlates well with the increase in net protein balance across the leg.

Children Under 4 Years Are at Greater Risk of Mortality Following Acute Burn Injury

“…Recent advances in adjunctive treatments, such as the use of beta blockers and oxandrolone, were less likely to be applied to patients during the study period than in the present. Beta blockers attenuate hypermetabolic states in children with burn injuries (16), and limited evidence from an adult sample suggests that they may potentially improve outcomes, including mortality (17). Although the effect of oxandrolone treatment on mortality has not been investigated, the use of oxandrolone with severely burned children has been shown to improve muscle protein metabolism, lean body mass, and bone mineral content and to reduce acute phase protein levels (18Y 21).…”

Restoration of Function

“…4 A recent study afforded by participation in a large multisite study 9 allowed identification of six genes up-regulated and two genes down-regulated with the administration of propranolol to burned children, suggesting the eventual possibility of targeting our interventions with greater specificity. 10 Burn injury also results in severe deconditoning and fatigue that can significantly impact functional aptitude. A 3-year outcome study at Harborview Medical Center in Seattle, Washington, revealed an almost-universal complaint of fatigue as a major barrier to return to work and other daily activities.…”

Comparative Proteomics Analysis of Vascular Smooth Muscle Cells Incubated with S- and R-Enantiomers of Atenolol Using iTRAQ-coupled Two-dimensional LC-MS/MS

“…To date most ␤-blockers are administered as the racemic mixture, although only the S-enantiomer is active at the receptor. The mechanism of action of ␤-blockers has been studied at the gene expression level (14). However, little is known about their action at the protein level.…”