NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions

Abstract

NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased NF-κB activity in the pathogenesis of insulin resistance and muscle atrophy. However, it is unclear whether insulin-resistant human subjects have abnormal NF-κB activity in muscle. The effect that exercise has on NF-κB activity/signaling also is not clear. We measured NF-κB DNA-binding activity and the mRNA level of putative NF-κB-regulated myokines interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) in muscle samples from T2DM, obese, and lean subjects immediately before, during (40 min), and after (210 min) a bout of moderate-intensity cycle exercise. At baseline, NF-κB activity was elevated 2.1- and 2.7-fold in obese nondiabetic and T2DM subjects, respectively. NF-κB activity was increased significantly at 210 min following exercise in lean (1.9-fold) and obese (2.6-fold) subjects, but NF-κB activity did not change in T2DM. Exercise increased MCP-1 mRNA levels significantly in the three groups, whereas IL-6 gene expression increased significantly only in lean and obese subjects. MCP-1 and IL-6 gene expression peaked at the 40-min exercise time point. We conclude that insulin-resistant subjects have increased basal NF-κB activity in muscle. Acute exercise stimulates NF-κB in muscle from nondiabetic subjects. In T2DM subjects, exercise had no effect on NF-κB activity, which could be explained by the already elevated NF-κB activity at baseline. Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-κB activity, suggesting that other factors promote gene expression of these cytokines during exercise.

Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight

“…Our study participants were generally insulin sensitive, so the association between insulin sensitivity and MCP1 expression may not be evident in this population. By contrast, the range in BMI was relatively broad (19-30 kg/m 2 ), suggesting that muscle MCP1 expression is unaffected by adiposity in normal and over weight individuals, similar to previous findings in lean and obese (28). Altogether, it seems that MCP1 expression in adipose tissue is dependent on body composition (49), whereas it is regulated by other, as yet unidentified, factors in skeletal muscle.…”

“…However, as MCP1 protein content was not measured, we cannot exclude that the increased macrophage infiltration could, at least partly, be a consequence of elevated muscle MCP1 protein levels. Acute exercise in humans and rodents increases muscle MCP1 mRNA expression (28,48). Similarly, we found increased MCP1 expression after retraining in NBW subjects.…”

“…Similarly, we found increased MCP1 expression after retraining in NBW subjects. Whether MCP1 expression is involved in mediating some metabolic effects of exercise in skeletal muscle, including angiogenesis as previously suggested (28,48), needs to be further investigated in human studies. However, our study indicates that the mechanism does not include recruitment of macrophages, as CD68 expression was unaffected by retraining.…”

“…Although not supported by all observations (24,25), several studies have implicated activity of the inflammatory inhibitor kB kinase (IKK)/nuclear factor-kB (NF-kB) pathway in skeletal muscle in the pathogenesis of insulin resistance (18,26,27,28,29). The transcription factor NF-kB induces expression of pro-inflammatory genes, including tumor necrosis factor-a (TNF-a), interleukin-6 (IL6), and monocyte chemotactic protein-1 (MCP1 (CCL2)) as well as the TNF-a receptor (30,31).…”

Simultaneous Effect of Resistance Training and Portulace Oleraceal Supplementation on Some Biochemical Markers of Bone Dynamics in Women with Type II Diabetes

“…Meanwhile, the amount of RANKL in this group decreased, and the rate of osteoporosis in the control group was higher than the training group after a year (22). (52). On the other hand, diabetic individuals have the highest level of NFκB activity, therefore it is likely that exercise may not increase the activity of NFκB because the threshold has been already triggered (47,54).…”