title: 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 specifically contribute to a disease phenotype. Aerobic exercise training represents a plausible model for identification 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 approximately 470 differentially regulated genes using the Affymetrix U95 platform (80 individual hybridization steps). Gene ontology analysis indicated that extracellular matrix and calcium binding gene families were most up-regulated after training. An electronic reanalysis of a Duchenne muscular dystrophy (DMD) transcript expression dataset allowed us to identify approximately 90 genes modulated in a nearly identical fashion to that observed in the endurance exercise dataset. Trophoblast 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 alpha7beta1 integrin signaling, and specific genes in this signaling pathway were up-regulated in both datasets. In contrast to these common features, OXPHOS gene expression is subdued in DMD yet elevated by exercise, indicating that more than one major mechanism must exist in human skeletal muscle to sense activity and therefore regulate gene expression. Exercise training modulated diabetes-related genes, suggesting our dataset may contain additional and novel gene expression changes relevant for the anti-diabetic properties of exercise. In conclusion, gene expression profiling 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 previously suggested as being important for the DMD disease phenotype may principally reflect compensatory integrin signaling.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Jamie.Timmons@fyfa.ki.se
authors.forename: James A
authors.initials: JA
authors.lastname: Timmons
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Eva
authors.initials: E
authors.lastname: Jansson
authors.forename: Helene
authors.initials: H
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Gustafsson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.forename: John
authors.initials: J
authors.lastname: Ridden
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rachman
authors.forename: Myriam
authors.initials: M
authors.lastname: Peyrard-Janvid
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Carl Johan
authors.initials: CJ
authors.lastname: Sundberg
mesh_terms: D001706:Biopsy; D002135:Calcium-Binding Proteins / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D015444:Exercise; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006339:Heart Rate; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010807:Physical Endurance / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013548:Sweden
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger