CLINICAL STUDY Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight Martin Friedrichsen 1,2,3 , Rasmus Ribel-Madsen 1 , Brynjulf Mortensen 1 , Christina N Hansen 2,4 , Amra C Alibegovic 1 , Lise Højbjerre 2,4 , Mette P Sonne 2,4 , Jørgen F P Wojtaszewski 3 , Bente Stallknecht 2 , Flemming Dela 2,4 and Allan Vaag 1,5 1 Steno Diabetes Center, Gentofte, Denmark, 2 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, 3 Molecular Physiology Group, Department of Exercise and Sport Sciences, The August Krogh Centre, Universityof Copenhagen, Universitetsparken 13, DK-2100 Copenhagen, Denmark, 4 Center for Healthy Ageing, University of Copenhagen, Copenhagen, Denmark and 5 Rigshospitalet, Department of Diabetes and Metabolism, Copenhagen, Denmark (Correspondence should be addressed to M Friedrichsen at Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen; Email: martin.friedrichsen@ifi.ku.dk) Abstract Objective: The molecular mechanisms linking physical inactivity and muscle insulin resistance in humans have been suggested to include increased muscle inflammation, possibly associated with impaired oxidative metabolism. We employed a human bed rest study including 20 young males with normal birth weight (NBW) and 20 with low birth weight (LBW) and increased risk of diabetes. Methodology: The subjects were studied before and after 9 days of bed rest using the euglycemic– hyperinsulinemic clamp and muscle biopsy excision. Muscle inflammatory status was assessed as nuclear factor-kB (NF-kB) activity and mRNA expression of the pro-inflammatory MCP1 (CCL2) and IL6 and the macrophage marker CD68. Furthermore, mRNA expression of genes central to oxidative phosphorylation (OXPHOS) was measured including ATP5O, COX7A1, NDUFB6, and UQCRB. Results: At baseline, muscle inflammatory status was similar in NBW and LBW individuals. After bed rest, CD68 expression was increased in LBW (PZ0.03) but not in NBW individuals. Furthermore, expression levels of all OXPHOS genes were reduced after bed rest in LBW (P%0.05) but not in NBW subjects and were negatively correlated with CD68 expression in LBW subjects (P%0.03 for all correlations). MCP1 expression and NF-kB activity were unaffected by bed rest, and IL6 expression was too low for accurate measurements. None of the inflammatory markers correlated with insulin sensitivity. Conclusions: Although LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest, our data altogether do not support the notion that bed rest-induced (9 days) insulin resistance is caused by increased muscle inflammation. European Journal of Endocrinology 167 829–838 Introduction Insulin resistance is a major component of type 2 diabetes (T2D) (1). Apart from a well-documented genetic influence (2, 3), insulin sensitivity is largely determined by age (4), sex (5), body composition/ adiposity (6), and physical activity level (7). In addition, an adverse intra-uterine environment, as evidenced by low birth weight (LBW), has consistently been associ- ated with altered metabolic function in studies of both young and old individuals (8, 9, 10, 11). The prevalence of T2D has increased rapidly over the last decades (12). This has, to a great extent, been attributed to an increasingly sedentary lifestyle (13, 14, 15). Muscle insulin resistance may represent a key mechanism linking physical inactivity with increased risk of developing T2D and may, to some extent, involve increased inflammation (13, 16, 17). Indeed, several studies have demonstrated that increased insulin sensitivity following exercise training was related to decreased muscle and/or systemic inflammation (18, 19). Thus, increased physical activity might, at least in part, increase insulin sensitivity by lowering the level of muscle inflammation. Although studies exam- ining the association between physical activity, insulin resistance, and inflammation are very important from an intervention perspective, most present societies become increasingly sedentary. Thus, a more relevant European Journal of Endocrinology (2012) 167 829–838 ISSN 0804-4643 q 2012 European Society of Endocrinology DOI: 10.1530/EJE-12-0498 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 06/05/2020 09:08:26PM via free access