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

Zderic TW, Hamilton MT - Lipids Health Dis (2012)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inactivity Physiology Department, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. theodore.zderic@pbrc.edu

ABSTRACT

Background: Partly 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.

Methods: Microarray 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.

Results: These 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.

Conclusions: These 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.

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Relationship between hemostatic gene function, physical inactivity, LPP1 and risk of deep venous thrombosis. Human skeletal muscle expresses distinct groups of genes involved in hemostasis (fibrinolysis, anti-coagulation, and coagulation factors, and enzymes involved in the synthesis of these factors). Of all these genes expressed in skeletal muscle, only LPP1 expression was affected by physical inactivity (i.e., sitting in humans). Sitting in humans and the removal of standing in rats suppressed LPP1 expression in skeletal muscle tissue. Prior studies have indicated that DVT is a complex disorder and caused by many interacting factors. We propose the novel hypothesis that the local gene expression deep in skeletal muscle could be a contributing factor. Many candidate genes known to regulate platelet aggregation and fibrin deposition are presently reported to be expressed in muscle tissues (Tables1 and2) and are presented here as four distinct groups. While some of those could be regulated post-transcriptionally, LPP1 mRNA was significantly decreased by physical inactivity. Prior published work indicates that LPP1 attenuates platelet aggregation, fibrin deposition, and inflammation. Ordinary non-exercise movements and standing, unlike the less frequent and higher intensity type of exercise more commonly associated with a boost in muscular strength or cardiovascular fitness, prevent the decrease in LPP1 expression. Items in red would favor a prothrombotic state while those in blue would be anti-thrombotic.
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Figure 6: Relationship between hemostatic gene function, physical inactivity, LPP1 and risk of deep venous thrombosis. Human skeletal muscle expresses distinct groups of genes involved in hemostasis (fibrinolysis, anti-coagulation, and coagulation factors, and enzymes involved in the synthesis of these factors). Of all these genes expressed in skeletal muscle, only LPP1 expression was affected by physical inactivity (i.e., sitting in humans). Sitting in humans and the removal of standing in rats suppressed LPP1 expression in skeletal muscle tissue. Prior studies have indicated that DVT is a complex disorder and caused by many interacting factors. We propose the novel hypothesis that the local gene expression deep in skeletal muscle could be a contributing factor. Many candidate genes known to regulate platelet aggregation and fibrin deposition are presently reported to be expressed in muscle tissues (Tables1 and2) and are presented here as four distinct groups. While some of those could be regulated post-transcriptionally, LPP1 mRNA was significantly decreased by physical inactivity. Prior published work indicates that LPP1 attenuates platelet aggregation, fibrin deposition, and inflammation. Ordinary non-exercise movements and standing, unlike the less frequent and higher intensity type of exercise more commonly associated with a boost in muscular strength or cardiovascular fitness, prevent the decrease in LPP1 expression. Items in red would favor a prothrombotic state while those in blue would be anti-thrombotic.

Mentions: The new knowledge that LPP1 is expressed in leg tissue differentially by physical activity patterns is significant because it provides the first study we are aware of on the physiological regulation of this gene. LPP1 mRNA encodes a 32 kDa transmembrane ecto-enzyme responsible for the degradation of the extracellular bioactive phospholipids by dephosphorylation. Lysophosphatidic acid (LPA), sphingosine-1-phosphate, ceramide-1-phosphate, and phosphatidic acid are all substrates for LPP1. LPA is arguably the most important of these lipids because it has the highest affinity for LPP1, and even more importantly, because LPA has recently emerged as a potent stimulator of platelet aggregation[20,22-25], platelet monocyte aggregation[20], tissue factor expression[26], fibronectin matrix[27], and inflammation[21,28,29]. Similarly, sphingosine-1-phosphate has been shown to stimulate platelets to bind and assemble fibronectin[27], stimulate tissue factor expression[31], and inflammation[28]. Both LPA and sphingosine-1-phosphate are released from activated platelets and are thought to promote a positive feedback on platelet aggregation. Haseruck et al.[20] argued that the expression of LPP1 on the endothelium of tissues (such as the endothelium in muscle tissue) would attenuate local accumulation of LPA and thus limit platelet activation[20]. In cell culture experiments where LPP1 expression has been manipulated, LPP1 has been shown to be important for the attenuation of several atherothrombogenic and malignant processes induced by LPA, including platelet aggregation[25], the release of the proinflammatory cytokine IL-8[22], and ovarian cancer cell proliferation[32]. There are several lines of evidence that LPP1 can also attenuate the signaling of other factors including the prothrombotic and proinflammatory cytokine TNFα[21] and thrombin[19]. Therefore, if the protein is regulated by its gene expression, LPP1 would be a novel candidate for why physical inactivity is a risk factor for DVT or other types of thrombosis (Figure6).


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

Zderic TW, Hamilton MT - Lipids Health Dis (2012)

Relationship between hemostatic gene function, physical inactivity, LPP1 and risk of deep venous thrombosis. Human skeletal muscle expresses distinct groups of genes involved in hemostasis (fibrinolysis, anti-coagulation, and coagulation factors, and enzymes involved in the synthesis of these factors). Of all these genes expressed in skeletal muscle, only LPP1 expression was affected by physical inactivity (i.e., sitting in humans). Sitting in humans and the removal of standing in rats suppressed LPP1 expression in skeletal muscle tissue. Prior studies have indicated that DVT is a complex disorder and caused by many interacting factors. We propose the novel hypothesis that the local gene expression deep in skeletal muscle could be a contributing factor. Many candidate genes known to regulate platelet aggregation and fibrin deposition are presently reported to be expressed in muscle tissues (Tables1 and2) and are presented here as four distinct groups. While some of those could be regulated post-transcriptionally, LPP1 mRNA was significantly decreased by physical inactivity. Prior published work indicates that LPP1 attenuates platelet aggregation, fibrin deposition, and inflammation. Ordinary non-exercise movements and standing, unlike the less frequent and higher intensity type of exercise more commonly associated with a boost in muscular strength or cardiovascular fitness, prevent the decrease in LPP1 expression. Items in red would favor a prothrombotic state while those in blue would be anti-thrombotic.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539950&req=5

Figure 6: Relationship between hemostatic gene function, physical inactivity, LPP1 and risk of deep venous thrombosis. Human skeletal muscle expresses distinct groups of genes involved in hemostasis (fibrinolysis, anti-coagulation, and coagulation factors, and enzymes involved in the synthesis of these factors). Of all these genes expressed in skeletal muscle, only LPP1 expression was affected by physical inactivity (i.e., sitting in humans). Sitting in humans and the removal of standing in rats suppressed LPP1 expression in skeletal muscle tissue. Prior studies have indicated that DVT is a complex disorder and caused by many interacting factors. We propose the novel hypothesis that the local gene expression deep in skeletal muscle could be a contributing factor. Many candidate genes known to regulate platelet aggregation and fibrin deposition are presently reported to be expressed in muscle tissues (Tables1 and2) and are presented here as four distinct groups. While some of those could be regulated post-transcriptionally, LPP1 mRNA was significantly decreased by physical inactivity. Prior published work indicates that LPP1 attenuates platelet aggregation, fibrin deposition, and inflammation. Ordinary non-exercise movements and standing, unlike the less frequent and higher intensity type of exercise more commonly associated with a boost in muscular strength or cardiovascular fitness, prevent the decrease in LPP1 expression. Items in red would favor a prothrombotic state while those in blue would be anti-thrombotic.
Mentions: The new knowledge that LPP1 is expressed in leg tissue differentially by physical activity patterns is significant because it provides the first study we are aware of on the physiological regulation of this gene. LPP1 mRNA encodes a 32 kDa transmembrane ecto-enzyme responsible for the degradation of the extracellular bioactive phospholipids by dephosphorylation. Lysophosphatidic acid (LPA), sphingosine-1-phosphate, ceramide-1-phosphate, and phosphatidic acid are all substrates for LPP1. LPA is arguably the most important of these lipids because it has the highest affinity for LPP1, and even more importantly, because LPA has recently emerged as a potent stimulator of platelet aggregation[20,22-25], platelet monocyte aggregation[20], tissue factor expression[26], fibronectin matrix[27], and inflammation[21,28,29]. Similarly, sphingosine-1-phosphate has been shown to stimulate platelets to bind and assemble fibronectin[27], stimulate tissue factor expression[31], and inflammation[28]. Both LPA and sphingosine-1-phosphate are released from activated platelets and are thought to promote a positive feedback on platelet aggregation. Haseruck et al.[20] argued that the expression of LPP1 on the endothelium of tissues (such as the endothelium in muscle tissue) would attenuate local accumulation of LPA and thus limit platelet activation[20]. In cell culture experiments where LPP1 expression has been manipulated, LPP1 has been shown to be important for the attenuation of several atherothrombogenic and malignant processes induced by LPA, including platelet aggregation[25], the release of the proinflammatory cytokine IL-8[22], and ovarian cancer cell proliferation[32]. There are several lines of evidence that LPP1 can also attenuate the signaling of other factors including the prothrombotic and proinflammatory cytokine TNFα[21] and thrombin[19]. Therefore, if the protein is regulated by its gene expression, LPP1 would be a novel candidate for why physical inactivity is a risk factor for DVT or other types of thrombosis (Figure6).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inactivity Physiology Department, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. theodore.zderic@pbrc.edu

ABSTRACT

Background: Partly 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.

Methods: Microarray 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.

Results: These 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.

Conclusions: These 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.

Show MeSH
Related in: MedlinePlus