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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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Interaction of genes involved in lysophospholipid metabolism. The novel finding is that skeletal muscle tissue expresses the genes regulating these pathways. The enzymes are in boxes and each is known to catalyze the reaction in the figure. The new data demonstrates that skeletal muscle tissue expresses a key LPA receptor (EDG2), and expresses a Rho kinase (ROCK2) well-known to be activated by LPA. In addition to platelet aggregation, ROCK2 has been associated with inflammation. The red pathway indicates a pathway to inflammation and the blue pathways would lead to an attenuation of LPA effects. Of these genes, only LPP1 is affected by physical inactivity. Abbreviations: LPC, lysophosphatidylcholine; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; EDG2, endothelial differentiation gene 2; LPP, lipid phosphate phosphatase; LYPLA, lysophospholipase; ROCK2, Rho-associated, coiled-coil containing protein kinase 2.
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Figure 5: Interaction of genes involved in lysophospholipid metabolism. The novel finding is that skeletal muscle tissue expresses the genes regulating these pathways. The enzymes are in boxes and each is known to catalyze the reaction in the figure. The new data demonstrates that skeletal muscle tissue expresses a key LPA receptor (EDG2), and expresses a Rho kinase (ROCK2) well-known to be activated by LPA. In addition to platelet aggregation, ROCK2 has been associated with inflammation. The red pathway indicates a pathway to inflammation and the blue pathways would lead to an attenuation of LPA effects. Of these genes, only LPP1 is affected by physical inactivity. Abbreviations: LPC, lysophosphatidylcholine; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; EDG2, endothelial differentiation gene 2; LPP, lipid phosphate phosphatase; LYPLA, lysophospholipase; ROCK2, Rho-associated, coiled-coil containing protein kinase 2.

Mentions: In addition to LPP1, there are several other lysophospholipid regulating genes expressed in skeletal muscle (Table3 and Figure5). Another isoform of LPP1, lipid phosphate phosphatase-3 (LPP3/PAP2B) was also significantly expressed above background (p < 0.05), although not significantly affected by physical inactivity. Lysophosphatidic acid (LPA) is putatively one of the key lipids involved in hemostasis, and is a substrate for LPP1. Two enzymes involved in LPA synthesis, lysophospholipase I (LYPLA1) and lysophospholipase II (LYPLA2), were significantly expressed in tandem with other genes in this pathway (p < 0.05). Three enzymes responsible for the transformation of LPA to phosphatidic acid (an initial step in triglyceride synthesis), lysophosphatidic acid acyltransferase-alpha (AGPAT1), lysophosphatidic acid acyltransferase-beta (AGPAT2), and lysophosphatidic acid acyltransferase-delta (AGPAT3) were significantly expressed. Of the LPA receptors (EDG2, EDG3, EDG4, EDG7) and the S-1-P receptor (EDG8), only EDG2 ([19] LPA1 receptor) was moderately expressed in human skeletal muscle. The current understanding of the relationship between these genes is schematically represented in Figure5.


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)

Interaction of genes involved in lysophospholipid metabolism. The novel finding is that skeletal muscle tissue expresses the genes regulating these pathways. The enzymes are in boxes and each is known to catalyze the reaction in the figure. The new data demonstrates that skeletal muscle tissue expresses a key LPA receptor (EDG2), and expresses a Rho kinase (ROCK2) well-known to be activated by LPA. In addition to platelet aggregation, ROCK2 has been associated with inflammation. The red pathway indicates a pathway to inflammation and the blue pathways would lead to an attenuation of LPA effects. Of these genes, only LPP1 is affected by physical inactivity. Abbreviations: LPC, lysophosphatidylcholine; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; EDG2, endothelial differentiation gene 2; LPP, lipid phosphate phosphatase; LYPLA, lysophospholipase; ROCK2, Rho-associated, coiled-coil containing protein kinase 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Interaction of genes involved in lysophospholipid metabolism. The novel finding is that skeletal muscle tissue expresses the genes regulating these pathways. The enzymes are in boxes and each is known to catalyze the reaction in the figure. The new data demonstrates that skeletal muscle tissue expresses a key LPA receptor (EDG2), and expresses a Rho kinase (ROCK2) well-known to be activated by LPA. In addition to platelet aggregation, ROCK2 has been associated with inflammation. The red pathway indicates a pathway to inflammation and the blue pathways would lead to an attenuation of LPA effects. Of these genes, only LPP1 is affected by physical inactivity. Abbreviations: LPC, lysophosphatidylcholine; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; EDG2, endothelial differentiation gene 2; LPP, lipid phosphate phosphatase; LYPLA, lysophospholipase; ROCK2, Rho-associated, coiled-coil containing protein kinase 2.
Mentions: In addition to LPP1, there are several other lysophospholipid regulating genes expressed in skeletal muscle (Table3 and Figure5). Another isoform of LPP1, lipid phosphate phosphatase-3 (LPP3/PAP2B) was also significantly expressed above background (p < 0.05), although not significantly affected by physical inactivity. Lysophosphatidic acid (LPA) is putatively one of the key lipids involved in hemostasis, and is a substrate for LPP1. Two enzymes involved in LPA synthesis, lysophospholipase I (LYPLA1) and lysophospholipase II (LYPLA2), were significantly expressed in tandem with other genes in this pathway (p < 0.05). Three enzymes responsible for the transformation of LPA to phosphatidic acid (an initial step in triglyceride synthesis), lysophosphatidic acid acyltransferase-alpha (AGPAT1), lysophosphatidic acid acyltransferase-beta (AGPAT2), and lysophosphatidic acid acyltransferase-delta (AGPAT3) were significantly expressed. Of the LPA receptors (EDG2, EDG3, EDG4, EDG7) and the S-1-P receptor (EDG8), only EDG2 ([19] LPA1 receptor) was moderately expressed in human skeletal muscle. The current understanding of the relationship between these genes is schematically represented in Figure5.

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