Upregulation of skeletal muscle inflammatory genes links inflammation with insulin resistance in women with the metabolic syndrome.

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

The identification of genetic pathways involved in vascular adaptations after physical deconditioning versus exercise training in humans.

Physical inactivity and exercise training result in opposite adaptations of vascular structure. However, the molecular mechanisms behind these adaptations are not completely understood. We used a unique study design to examine both vascular characteristics of the superficial femoral artery (using ultrasound) and gene expression levels (from a muscle biopsy) in human models for physical deconditioning and exercise training. Initially, we compared able-bodied control subjects (n = 6) with spinal cord-injured individuals (n = 8) to assess the effects of long-term deconditioning. Subsequently, able-bodied control subjects underwent short-term lower limb deconditioning using 3 weeks of unilateral limb suspension. Spinal cord-injured individuals were examined before and after 6 weeks of functional electrical stimulation exercise training. Baseline femoral artery diameter and hyperaemic flow were lower after short- and long-term deconditioning and higher after exercise training, whilst intima-media thickness/lumen ratio was increased with short- and long-term deconditioning and decreased with exercise training. Regarding gene expression levels of vasculature-related genes, we found that groups of genes including the vascular endothelial growth factor pathway, transforming growth factor ß1 and extracellular matrix proteins were strongly associated with vascular adaptations in humans. This approach resulted in the identification of important genes that may be involved in vascular adaptations after physical deconditioning and exercise.

Expression of genes involved in fatty acid transport and insulin signaling is altered by physical inactivity and exercise training in human skeletal muscle.

Physical deconditioning is associated with the development of chronic diseases, including type 2 diabetes and cardiovascular disease. Exercise training effectively counteracts these developments, but the underlying mechanisms are largely unknown. To gain more insight into these mechanisms, muscular gene expression levels were assessed after physical deconditioning and after exercise training of the lower limbs in humans by use of gene expression microarrays. To exclude systemic effects, we used human models for local physical inactivity (3 wk of unilateral limb suspension) and for local exercise training (6 wk of functional electrical stimulation exercise of the extremely deconditioned legs of individuals with a spinal cord injury). The most interesting subset of genes, those downregulated after deconditioning as well as upregulated after exercise training, contained 18 genes related to both the "insulin action" and "adipocytokine signaling" pathway. Of these genes, the three with strongest up/downregulation were the muscular fatty acid-binding protein-3 (FABP3), the fatty acid oxidizing enzyme hydroxyacyl-CoA dehydrogenase (HADH), and the mitochondrial fatty acid transporter solute carrier 25 family member A20 (SLC25A20). The expression levels of these genes were confirmed using RT-qPCR. The results of the present study indicate an important role for a decreased transport and metabolism of fatty acids, which provides a link between physical activity levels and insulin signaling.