Identification of hemostatic genes expressed in human and rat leg muscles and a novel gene (LPP1/PAP2A) suppressed during prolonged physical inactivity (sitting)

Abstract

BackgroundPartly because of functional genomics, there has been a major paradigm shift from solely thinking of skeletal muscle as contractile machinery to an understanding that it can have roles in paracrine and endocrine functions. Physical inactivity is an established risk factor for some blood clotting disorders. The effects of inactivity during sitting are most alarming when a person develops the enigmatic condition in the legs called deep venous thrombosis (DVT) or “coach syndrome,” caused in part by muscular inactivity. The goal of this study was to determine if skeletal muscle expresses genes with roles in hemostasis and if their expression level was responsive to muscular inactivity such as occurs in prolonged sitting.MethodsMicroarray analyses were performed on skeletal muscle samples from rats and humans to identify genes associated with hemostatic function that were significantly expressed above background based on multiple probe sets with perfect and mismatch sequences. Furthermore, we determined if any of these genes were responsive to models of physical inactivity. Multiple criteria were used to determine differential expression including significant expression above background, fold change, and non-parametric statistical tests.ResultsThese studies demonstrate skeletal muscle tissue expresses at least 17 genes involved in hemostasis. These include the fibrinolytic factors tetranectin, annexin A2, and tPA; the anti-coagulant factors TFPI, protein C receptor, PAF acetylhydrolase; coagulation factors, and genes necessary for the posttranslational modification of these coagulation factors such as vitamin K epoxide reductase. Of special interest, lipid phosphate phosphatase-1 (LPP1/PAP2A), a key gene for degrading prothrombotic and proinflammatory lysophospholipids, was suppressed locally in muscle tissue within hours after sitting in humans; this was also observed after acute and chronic physical inactivity conditions in rats, and exercise was relatively ineffective at counteracting this effect in both species.ConclusionsThese findings suggest that skeletal muscle may play an important role in hemostasis and that muscular inactivity may contribute to hemostatic disorders not only because of the slowing of blood flow per se, but also potentially because of the contribution from genes expressed locally in muscles, such as LPP1.

Dose–response relationships between sedentary behaviour and the metabolic syndrome and its components

“…This notion is supported in a review of several studies by Hamilton et al [29], who demonstrated that the expression of some genes important for preventing diabetes and other metabolic risks is resistant to being restored after 12 h of inactivity, while the expression of others is not. In particular, a study examining the activity of lipid phosphate phosphatase-1 (LPP1) suggested that gene expression may be suppressed in response to chronic sitting despite participation in 1 h/day of vigorous exercise [30].…”

Motor-Driven (Passive) Cycling

“…In fact, passive cycling increases EE more than other commonly proposed sitting interventions like standing or sitting on an exercise ball (3). Furthermore, muscle activity is associated with changes to other cardiometabolic risk factors like HDL and triglycerides (30), lipoprotein lipase (7), and genes involved with overall homeostasis (38). It is possible that passive cycling may lower these other cardiometabolic risk factors and help to further counteract the deleterious effects of sitting; something that should be examined in longer term follow-up studies.…”

Occupational Sedentary Behavior and Solutions to Increase Non-Exercise Activity Thermogenesis

“…Breaking up the workstation sitting by 2 min of walking at ~2mph three times an hour reduced the development of blood factors that promote pro-coagulation and the risk of thrombosis (Howard et al 2013). A case study of one individual and analyses of the animal tissue showed that subsequent bouts of physical activity did not reverse the suppression of lipid phosphate phosphatase-1, which would have a protective effect by degrading factors that promote thrombosis (Zderic and Hamilton 2012). This again suggests that intermittent activity to break up prolonged sitting is important, in this case to prevent hemostasis and risks of thrombosis.…”

“…More commonly thought of as a health concern for elderly and those doing prolonged air travel, the case study of a 32-y old male who spent extensive time motionless at a computer station brought the issue to light (Beasley, Raymond, Hill, Nowitz, & Hughes, 2003). Subsequent experimental research identified hematopoetic changes and the expression of skeletal muscle genes that could contribute to the development of thrombosis as a result of physical inactivity brought on by prolonged sitting or simulation of prolonged sitting (Howard et al 2013;Zderic and Hamilton 2012). Breaking up the workstation sitting by 2 min of walking at ~2mph three times an hour reduced the development of blood factors that promote pro-coagulation and the risk of thrombosis (Howard et al 2013).…”