Gene expression profiles and protein balance in skeletal muscle of burned children after beta-adrenergic blockade.
Propranolol, a nonselective beta-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.
Herndon
David N
DN
Department of Surgery, the University of Texas Medical Branch, 815 Market Street, Galveston, TX 77550, USA.
Dasu
Mohan R K
MR
Wolfe
Robert R
RR
Barrow
Robert E
RE
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D002056:Burns / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values
D000319:Adrenergic beta-Antagonists; D009124:Muscle Proteins; D011433:Propranolol