Gene expression profile in the diaphragm following contractile inactivity during thoracic surgery

Introduction. Recent work revealed the development of marked muscle fiber weakness in the diaphragm, but not in the non-respiratory latissimus dorsi, during thoracic surgery. To disentangle the molecular processes that underlie the development of diaphragm muscle fiber weakness during thoracic surgery, we studied changes in the gene expression profile. Methods. Serial biopsies from the diaphragm and the latissimus dorsi muscle were obtained from four patients during thoracotomy for resection of a tumor in the right lung. Biopsies were taken as soon as the diaphragm had been exposed (t0) and again after two hours (t2). Gobal differences in gene expression in diaphragm biopsies were assessed by microarray analysis. Results. 346 differentially expressed gene transcripts were found in the diaphragm at t2 vs. t0. Pathway analysis revealed that genes associated with inflammation (83 genes; p<0.0001) and cell death (118 genes, p<0.0001) pathways were significantly overexpressed at t2. Of the 346 differentially expressed genes in the diaphragm at t2, 258 were also differential in the latissimus dorsi muscle, with the direction of change being identical for all differentially expressed genes. In addition, latissimus dorsi showed exclusive upregulaton of negative regulators of cell death. Conclusions. Two hours of thoracic surgery result in rapid and profound changes in expression of inflammatory response and apoptotic genes in the diaphragm. The apoptotic response was stronger in the diaphragm than in the latissiums dorsi. These findings suggest that the development of selective diaphragm muscle fiber weakness in these patients might be related to an exaggerated apoptotic response.