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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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Case study on the effect of several levels of physical activity on LPP1 expression in deep human skeletal muscle. A healthy male subject (25 yrs.) was the tissue donor for all of the repeated measures treatments. The standing/ambulatory control day was normal to low-intensity puttering for 12 hours before the muscle biopsy. During the exercise day, the subject performed aerobic exercise (cycle ergometry and treadmill walking) in addition to normal spontaneous standing/ambulatory activity. For chronic inactivity, the subject sat in a wheelchair for 15 days and exercised one leg daily (but without adding back the natural standing and other low-intensity physical activity), while the other leg never received exercise. After 16 days of sitting, the subject returned to daily standing/ambulatory activity for 12 hours immediately preceding a final biopsy. Diet was controlled the day of and the day before all muscle biopsies which were all taken at the same time of day. Error bars are shown to indicate the variability (SD) between repeated biopsies on the same day.
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Figure 4: Case study on the effect of several levels of physical activity on LPP1 expression in deep human skeletal muscle. A healthy male subject (25 yrs.) was the tissue donor for all of the repeated measures treatments. The standing/ambulatory control day was normal to low-intensity puttering for 12 hours before the muscle biopsy. During the exercise day, the subject performed aerobic exercise (cycle ergometry and treadmill walking) in addition to normal spontaneous standing/ambulatory activity. For chronic inactivity, the subject sat in a wheelchair for 15 days and exercised one leg daily (but without adding back the natural standing and other low-intensity physical activity), while the other leg never received exercise. After 16 days of sitting, the subject returned to daily standing/ambulatory activity for 12 hours immediately preceding a final biopsy. Diet was controlled the day of and the day before all muscle biopsies which were all taken at the same time of day. Error bars are shown to indicate the variability (SD) between repeated biopsies on the same day.

Mentions: In the follow-up study to repeat these measurements over a more extensive time course, the decrease in LPP1 expression was complete within the first day (41% of control, 3rd bar in Figure4) and was not decreased further after 15 days (49% of control, 4th bar) of sitting in a wheelchair. During the chronic inactivity, this person exercised the left leg for one hour per day with cycle ergometry while the right leg never exercised. This daily exercise (i.e., 1 hr of vigorous cycling including intervals and resistance training, but no standing/ambulating) did not attenuate the decrease in LPP1 expression (5th bar, Figure4). Therefore, the effect of too much sitting overwhelmed any putative effects of exercise on LPP1. Furthermore, exercise was also ineffective in increasing LPP1 expression a month before the chronic inactivity (2nd bar, Figure4). We expected that LPP1 expression would return to normal following 12 hours of standing and ambulation after 16 days of sitting; it did not (56 ± 3% of standing control) (6th bar, Figure4).


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)

Case study on the effect of several levels of physical activity on LPP1 expression in deep human skeletal muscle. A healthy male subject (25 yrs.) was the tissue donor for all of the repeated measures treatments. The standing/ambulatory control day was normal to low-intensity puttering for 12 hours before the muscle biopsy. During the exercise day, the subject performed aerobic exercise (cycle ergometry and treadmill walking) in addition to normal spontaneous standing/ambulatory activity. For chronic inactivity, the subject sat in a wheelchair for 15 days and exercised one leg daily (but without adding back the natural standing and other low-intensity physical activity), while the other leg never received exercise. After 16 days of sitting, the subject returned to daily standing/ambulatory activity for 12 hours immediately preceding a final biopsy. Diet was controlled the day of and the day before all muscle biopsies which were all taken at the same time of day. Error bars are shown to indicate the variability (SD) between repeated biopsies on the same day.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Case study on the effect of several levels of physical activity on LPP1 expression in deep human skeletal muscle. A healthy male subject (25 yrs.) was the tissue donor for all of the repeated measures treatments. The standing/ambulatory control day was normal to low-intensity puttering for 12 hours before the muscle biopsy. During the exercise day, the subject performed aerobic exercise (cycle ergometry and treadmill walking) in addition to normal spontaneous standing/ambulatory activity. For chronic inactivity, the subject sat in a wheelchair for 15 days and exercised one leg daily (but without adding back the natural standing and other low-intensity physical activity), while the other leg never received exercise. After 16 days of sitting, the subject returned to daily standing/ambulatory activity for 12 hours immediately preceding a final biopsy. Diet was controlled the day of and the day before all muscle biopsies which were all taken at the same time of day. Error bars are shown to indicate the variability (SD) between repeated biopsies on the same day.
Mentions: In the follow-up study to repeat these measurements over a more extensive time course, the decrease in LPP1 expression was complete within the first day (41% of control, 3rd bar in Figure4) and was not decreased further after 15 days (49% of control, 4th bar) of sitting in a wheelchair. During the chronic inactivity, this person exercised the left leg for one hour per day with cycle ergometry while the right leg never exercised. This daily exercise (i.e., 1 hr of vigorous cycling including intervals and resistance training, but no standing/ambulating) did not attenuate the decrease in LPP1 expression (5th bar, Figure4). Therefore, the effect of too much sitting overwhelmed any putative effects of exercise on LPP1. Furthermore, exercise was also ineffective in increasing LPP1 expression a month before the chronic inactivity (2nd bar, Figure4). We expected that LPP1 expression would return to normal following 12 hours of standing and ambulation after 16 days of sitting; it did not (56 ± 3% of standing control) (6th bar, Figure4).

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