Human muscle gene expression responses to endurance training provide a novel perspective on Duchenne muscular dystrophy

Abstract

Global gene expression profiling is used to generate novel insight into a variety of disease states. Such studies yield a bewildering number of data points, making it a challenge to validate which genes specifi- cally contribute to a disease phenotype. Aerobic exer- cise training represents a plausible model for identifi- cation of molecular mechanisms that cause metabolic- related changes in human skeletal muscle. We carried out the first transcriptome-wide characterization of human skeletal muscle responses to 6 wk of supervised aerobic exercise training in 8 sedentary volunteers. Biopsy samples before and after training allowed us to identify 470 differentially regulated genes using the Affymetrix U95 platform (80 individual hybridization steps). Gene ontology analysis indicated that extracel- lular matrix and calcium binding gene families were most up-regulated after training. An electronic reanal- ysis of a Duchenne muscular dystrophy (DMD) tran- script expression dataset allowed us to identify 90 genes modulated in a nearly identical fashion to that observed in the endurance exercise dataset. Tropho- blast noncoding RNA, an interfering RNA species, was the singular exception— being up-regulated by exercise and down-regulated in DMD. The common overlap between gene expression datasets may be explained by enhanced 71 integrin signaling, and specific genes in this signaling pathway were up-regulated in both data- sets. In contrast to these common features, OXPHOS gene expression is subdued in DMD yet elevated by exercise, indicating that more than one major mecha- nism must exist in human skeletal muscle to sense activity and therefore regulate gene expression. Exer- cise training modulated diabetes-related genes, suggest- ing our dataset may contain additional and novel gene expression changes relevant for the anti-diabetic prop- erties of exercise. In conclusion, gene expression pro- filing after endurance exercise training identified a range of processes responsible for the physiological remodeling of human skeletal muscle tissue, many of which were similarly regulated in DMD. Furthermore, our analysis demonstrates that numerous genes previ- ously suggested as being important for the DMD dis- ease phenotype may principally reflect compensatory integrin signaling.—Timmons, J. A., Larsson, O., Jans- son, E., Fischer, H., Gustafsson, T., Greenhaff, P. L., Ridden, J., Rachman, J., Peyrard-Janvid, M., Wahlest- edt, C., Johan, C. Sundberg Human muscle gene ex- pression responses to endurance training provide a novel perspective on Duchenne muscular dystrophy. FASEB J. 19, 750 -760 (2005)