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.

Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

“…High density oligonucleotide microarrays have previously been utilized to characterize, e.g., age-or exercise-related changes in human skeletal muscle, [40][41][42][43][44][45][46][47][48][49] but not directly menopause-or HRT-related transcriptional changes. The transcriptome-wide effects of HRT have only been studied in blood samples from postmenopausal women.…”

“…However, similar 41,43,45,47,63 or even smaller 40,42,44,46,48 numbers of subjects have been successfully utilized in previous microarray studies investigating transcriptional changes in skeletal muscle. In our study, an extra strength is achieved by using RCT-design with repeatedmeasures analysis, which enables the detection of intra-individual changes in gene expression.…”

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

“…While the molecular mechanisms underpinning the benefits of exercise therapy are still poorly understood (22,23), there is little doubt that medical treatment for type 2 diabetes should include prescription of endurance exercise activities. Thus for optimal benefit, any new pharmacological agent should be compatible with exercise therapy.…”

Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

“…Muscular dystrophy is associated with a reduced skeletal muscle oxidative capacity [24]. Exercise improves muscle oxidative capacity in mdx mice [25,26], which as an adaptation could increase resistance to the dystrophic pathology [7].…”