PGC-1, exercise, metabolism and inflammation
Supermario
28 Jan 2011
A lot of articles have been published on PGC-1.
PGC-1 is induced by exercise. It mediates the majority of molecular events of exercise.
Pharmacologically, PGC-1 can be induced by clenbuterol.
I was pretended for a long time that PGC-1 exerts positive effects.
Now, more and more reports appear that correct this picture:
1) Zechner C et al, Cell metabolism 2010 shows that the loss of either PGC-1 alpha or beta has almost no effect on exercise performance. Only the loss of both, which results in impairments in mitochondrial development has an effect.
2)Miura S et al, Am J Pathol. 2006 showed atrophy in muscle in response to PGC-1 alpha.
3)Summermatter S et al, JBC 2010 demonstrated increased lipid accumulation in muscle of sedentary mice that overexpress PGC-1.
4) Olesen J et al, Medicine & Science in Sports & Exercise 2010 found elevated inflammation because PGC-1 induces TNFalpha production and secretion.
This finding fits well with the elevation of lipids see 3) which can also act pro-inflammatory.
In conclusion, PGC-1 is not only a good boy
PGC-1 is induced by exercise. It mediates the majority of molecular events of exercise.
Pharmacologically, PGC-1 can be induced by clenbuterol.
I was pretended for a long time that PGC-1 exerts positive effects.
Now, more and more reports appear that correct this picture:
1) Zechner C et al, Cell metabolism 2010 shows that the loss of either PGC-1 alpha or beta has almost no effect on exercise performance. Only the loss of both, which results in impairments in mitochondrial development has an effect.
2)Miura S et al, Am J Pathol. 2006 showed atrophy in muscle in response to PGC-1 alpha.
3)Summermatter S et al, JBC 2010 demonstrated increased lipid accumulation in muscle of sedentary mice that overexpress PGC-1.
4) Olesen J et al, Medicine & Science in Sports & Exercise 2010 found elevated inflammation because PGC-1 induces TNFalpha production and secretion.
This finding fits well with the elevation of lipids see 3) which can also act pro-inflammatory.
In conclusion, PGC-1 is not only a good boy
yoyo
06 Mar 2011
inflammation is anabolic. It goes back to very old, conserved mechanisms for growth or loss. See also insulin, cortisol, cyclooxengenase products, etc.
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andrea
23 Jul 2011
PGC-1 {alpha} and {beta} are activators of mitochondrial biogenesis and master regulators of muscle metabolism.
Recently, they have been suggested to modulate inflammatory responses. Studies were undertaken to unravel the role of PGC-1 on inflammatory
processes. Inflammation was induced by intramuscular injection of lipopolysaccharide (LPS) or tumour necrosis factor {alpha} (TNF{alpha}) into mice
transgenic for PGC-1 {alpha} or {beta}. The results show that: 1) Overexpression of PGC-1 exerts distinct inflammatory effects. On the one hand PGC
-1 reduces the basal levels of pro-inflammatory p65 (NF{kappa}B), while on the other hand it increases the basal levels of pro-inflammatory TNF
{alpha}. 2) Injection of LPS or TNF{alpha} lead to strong inflammation, but the differential pattern already observed at the basal state remains. 3)
LPS/TNF stimulate the infiltration of macrophages into muscle tissue more in transgenic than in wild-type mice. We conclude that PGC-1 does exert a
mixed effect on inflammation. overexpression of PGC-1 stimulate, but also represses pro-inflammatory markers. The data suggest that no direct
interaction between PGC-1 and inflammatory processes occurs. Rather, inflammation seems to occur secondarily and artefactually to the transgene
expression. Differences observed after stumilation by LPS/TNF represent carry-over effects of the artefactual changes in the basal state.
Recently, they have been suggested to modulate inflammatory responses. Studies were undertaken to unravel the role of PGC-1 on inflammatory
processes. Inflammation was induced by intramuscular injection of lipopolysaccharide (LPS) or tumour necrosis factor {alpha} (TNF{alpha}) into mice
transgenic for PGC-1 {alpha} or {beta}. The results show that: 1) Overexpression of PGC-1 exerts distinct inflammatory effects. On the one hand PGC
-1 reduces the basal levels of pro-inflammatory p65 (NF{kappa}B), while on the other hand it increases the basal levels of pro-inflammatory TNF
{alpha}. 2) Injection of LPS or TNF{alpha} lead to strong inflammation, but the differential pattern already observed at the basal state remains. 3)
LPS/TNF stimulate the infiltration of macrophages into muscle tissue more in transgenic than in wild-type mice. We conclude that PGC-1 does exert a
mixed effect on inflammation. overexpression of PGC-1 stimulate, but also represses pro-inflammatory markers. The data suggest that no direct
interaction between PGC-1 and inflammatory processes occurs. Rather, inflammation seems to occur secondarily and artefactually to the transgene
expression. Differences observed after stumilation by LPS/TNF represent carry-over effects of the artefactual changes in the basal state.
Boolean
08 Sep 2011
I love me some B2RA's. Albuterol is more my favorite, honestly. Has a shorter half-life.
PTerm
07 Mar 2012
REVIEW: PGC-1 and inflammation (PGC-1alpha, PGC-1beta)
In the meantime the roles of PGC-1 in inflammatory processes have been investigated in detail.
A very important article (http://www.plosone.o...al.pone.0032222) by Henriette Pilegaard, a leading scientist in the topic brought light into the action of PGC-1.
She found that PGC-1, which is activated in muscle by exercise, activates NF kappa B, alos known as p65. p65 phosphorylation is then increased. p65 increases the expression of TNF alpha.
Independently, other groups elucidated the mechanistic background:
-Romanino, K et al PNAS 2012 showed in the same rodent model of muscle specific overexpression of PGC-1 increases in skeletal muscle Akt protein levels. Akt, also known as Protein kinase B (PKB) is known to phosphorylate p65 (shown by two independent groups: Viatour, P et al Trends Biochem Sci 2005 and Chen, LF et al Nat Rev Mol Cell Biol 2004). Therefore, there is increased phosphorylation of p65 in muscle-specific transgenic mice.
-Summermatter, S et al AJP 2012 demonstrated in the same model that calcineurin activity is increased. Calcineurin activates p65 and this has directly been shown in muscle cells (shown by two independent groups: Harris, CD et al Cellular and Molecular Life Science 2005 and Alzuherri, H and Cheng KC Cell Signal 2003).
NF kappa B is an important mediator of inflammation.
The group of Henriette Pilegaard already in 2010 published an article in in Medicine & Science in Sports & Exercise where she examinded isolated myoblasts from the same mouse models with overexpression of PGC-1. With this advanced technique she could show that TNF alpha expression was higher in the presence of high PGC-1 levels and lower in the absence of PGC-1. That study was important to show that the effect was not caused by macrophage infiltration.
A recent publication looked at immortalized muscle cells infected with adenovirus overexpressing PGC-1 (http://www.plosone.o...al.pone.0029985). Normally, it doesn't make a lot of sense to study inflammation by adding a stron inflammatory virus, but they were very careful. So, they made sure to use the virus at the exactly same infection degree (same multiplicity of infection). That's was crucial, because only then they could be sure that the differential changes were not due to different viral loads.
They confirmed the above findings that PGC-1 leads to inflammation. They found upregulated genes for chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8 were upregulated.
All that was shown for PGC-1 alpha. Sure the same could be found for PGC-1 beta. But this cannot be tested because there is now good mouse model for PGC-1 beta. One exists, but the levels of PGC-1 beta are unphysiologically high.
The role of PGC-1 in inflammation is now clearly elucidated
In the meantime the roles of PGC-1 in inflammatory processes have been investigated in detail.
A very important article (http://www.plosone.o...al.pone.0032222) by Henriette Pilegaard, a leading scientist in the topic brought light into the action of PGC-1.
She found that PGC-1, which is activated in muscle by exercise, activates NF kappa B, alos known as p65. p65 phosphorylation is then increased. p65 increases the expression of TNF alpha.
Independently, other groups elucidated the mechanistic background:
-Romanino, K et al PNAS 2012 showed in the same rodent model of muscle specific overexpression of PGC-1 increases in skeletal muscle Akt protein levels. Akt, also known as Protein kinase B (PKB) is known to phosphorylate p65 (shown by two independent groups: Viatour, P et al Trends Biochem Sci 2005 and Chen, LF et al Nat Rev Mol Cell Biol 2004). Therefore, there is increased phosphorylation of p65 in muscle-specific transgenic mice.
-Summermatter, S et al AJP 2012 demonstrated in the same model that calcineurin activity is increased. Calcineurin activates p65 and this has directly been shown in muscle cells (shown by two independent groups: Harris, CD et al Cellular and Molecular Life Science 2005 and Alzuherri, H and Cheng KC Cell Signal 2003).
NF kappa B is an important mediator of inflammation.
The group of Henriette Pilegaard already in 2010 published an article in in Medicine & Science in Sports & Exercise where she examinded isolated myoblasts from the same mouse models with overexpression of PGC-1. With this advanced technique she could show that TNF alpha expression was higher in the presence of high PGC-1 levels and lower in the absence of PGC-1. That study was important to show that the effect was not caused by macrophage infiltration.
A recent publication looked at immortalized muscle cells infected with adenovirus overexpressing PGC-1 (http://www.plosone.o...al.pone.0029985). Normally, it doesn't make a lot of sense to study inflammation by adding a stron inflammatory virus, but they were very careful. So, they made sure to use the virus at the exactly same infection degree (same multiplicity of infection). That's was crucial, because only then they could be sure that the differential changes were not due to different viral loads.
They confirmed the above findings that PGC-1 leads to inflammation. They found upregulated genes for chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8 were upregulated.
All that was shown for PGC-1 alpha. Sure the same could be found for PGC-1 beta. But this cannot be tested because there is now good mouse model for PGC-1 beta. One exists, but the levels of PGC-1 beta are unphysiologically high.
The role of PGC-1 in inflammation is now clearly elucidated
karstensens
06 Jun 2012
Thanks a lot for that great REVIEW.
There is also a discussion about PGC-1 and macrophages.
From a scientific background I am sceptical because:
1) PGC-1 alpha and PGC-1 beta muscle transgenic mice have massively elevated angiogenesis and higher capillary densities than control wild-type animals (Arany Z et al, Nature 2008 for PGC-1alpha and Rowe GC et al, Am J Physiol Endocrinol Metab 2011 for PGC-1beta).
Therefore, there are much more blood and blood components (macrophages) in the muscles of those transgenic animals. Also there is more endothelial surface/volume available for the uptake of macrophages in those transgenic animals.
Differences observed when comparing blood components between control and transgenic animals might stem simply from the higher amount of blood in the muscles of transgenic animals or in the case of lower levels stem from the enhanced circulation. The differences are, however, NOT due to different levels of inflammation.
In addition, after removal of the muscles, there is higher probability of remaining blood residuals (macrophages) in those animals, because of the bigger blood vessel network.
This certainly occurs when the muscles are not extensively washed and freed from all blood in all capillaries and can never be excluded even if they are properly washed.
2) Real-time PCR is NOT an adequate tool to assess levels of pro- or antiinflammatory macrophage markers.
Real-time PCR is a method that leads to exponential amplification of any caught signal.
The presence of one or two macrophages (possibly due to the points discussed in 1)) can be catched by RT-PCR and will then be amplified exponentially by RT-PCR resulting in arteficially amplified differences, which are, however, not real.
3) When measuring macrophage genes by RT-PCR, it has to be mentioned, that compared to other genes in the muscle, the mRNA deriving from macrophages constitutes a negligible proportion.
The Ct values are therefore very high (low amounts of mRNA) and signals are normally detected at cycles much later than 34 when unspecific signals turn up as well.
There is extremely high probability that at such late cycles only primer dimer amplifactions or other artefacts are detected. Confirmation of protein expression by western blots is a must!
4) There are very few macrophages in muscle. Sometimes when histology is shown, a section is shown which is close to a site of injection and thus there are some macrophages.
Probably in a more distant region that would not be the case. It is thus important to really show the entire muscle cross-section to allow proper comparison.
5) Sometimes links between muscle inflammation and insulin resistance are established. It has to be considered that inflammation under this pathological state is mainly due to adipose tissue and NOT to skeletal muscle.
Moreover, inflammation in muscle is a consequence of obesity and NOT a cause of insulin resistance. Corresponding publications galore can be found.
So, what we can trust is is described in the REVIEW from previous author
There is also a discussion about PGC-1 and macrophages.
From a scientific background I am sceptical because:
1) PGC-1 alpha and PGC-1 beta muscle transgenic mice have massively elevated angiogenesis and higher capillary densities than control wild-type animals (Arany Z et al, Nature 2008 for PGC-1alpha and Rowe GC et al, Am J Physiol Endocrinol Metab 2011 for PGC-1beta).
Therefore, there are much more blood and blood components (macrophages) in the muscles of those transgenic animals. Also there is more endothelial surface/volume available for the uptake of macrophages in those transgenic animals.
Differences observed when comparing blood components between control and transgenic animals might stem simply from the higher amount of blood in the muscles of transgenic animals or in the case of lower levels stem from the enhanced circulation. The differences are, however, NOT due to different levels of inflammation.
In addition, after removal of the muscles, there is higher probability of remaining blood residuals (macrophages) in those animals, because of the bigger blood vessel network.
This certainly occurs when the muscles are not extensively washed and freed from all blood in all capillaries and can never be excluded even if they are properly washed.
2) Real-time PCR is NOT an adequate tool to assess levels of pro- or antiinflammatory macrophage markers.
Real-time PCR is a method that leads to exponential amplification of any caught signal.
The presence of one or two macrophages (possibly due to the points discussed in 1)) can be catched by RT-PCR and will then be amplified exponentially by RT-PCR resulting in arteficially amplified differences, which are, however, not real.
3) When measuring macrophage genes by RT-PCR, it has to be mentioned, that compared to other genes in the muscle, the mRNA deriving from macrophages constitutes a negligible proportion.
The Ct values are therefore very high (low amounts of mRNA) and signals are normally detected at cycles much later than 34 when unspecific signals turn up as well.
There is extremely high probability that at such late cycles only primer dimer amplifactions or other artefacts are detected. Confirmation of protein expression by western blots is a must!
4) There are very few macrophages in muscle. Sometimes when histology is shown, a section is shown which is close to a site of injection and thus there are some macrophages.
Probably in a more distant region that would not be the case. It is thus important to really show the entire muscle cross-section to allow proper comparison.
5) Sometimes links between muscle inflammation and insulin resistance are established. It has to be considered that inflammation under this pathological state is mainly due to adipose tissue and NOT to skeletal muscle.
Moreover, inflammation in muscle is a consequence of obesity and NOT a cause of insulin resistance. Corresponding publications galore can be found.
So, what we can trust is is described in the REVIEW from previous author
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Blättler
11 Jun 2012
Regarding PGC-1 and macrophages look at this info:
Mice transgenic for PGC-1 have massively elevated angiogenesis and higher capillary densities than control wild-type animals (Arany Z et al, Nature 2008 for PGC-1alpha and Rowe GC et al, Am J Physiol Endocrinol Metab 2011 for PGC-1beta). Therefore, there are much more blood and blood components (macrophages) in the muscles of those transgenic animals. Also there is more endothelial surface/volume available for the uptake of macrophages in those transgenic animals. This messes the whole thing even more up.
Finally, it has been demonstrated years ago (Yakeu et al, Atherosclerosis 2010) that PGC-1alpha and PGC-1beta mediate PPARγ/PGC-1α/β-driven macrophage M2 polarisation. M2 macrophages are more anti-inflammatory. PGC-1α and PGC-1β on the other hand were shown to downregulate pro-inflammatory M1 markers. Moreover, plasma levels of Th2 cytokines increased when PGC-1 was high, while those of Th1 cytokines decreased. Thus, PGC-1 may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARγ.
Already in 2006 Vats, D et al Cell Metabolism has shown that PGC-1 and oxidative metabolism promote M2 polarization of macrophages. They published that expression of PGC-1 primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response.
A more recent publication by Chan MM, PPAR Res, 2012 showed that PPAR gamma coactivator-1 (PGC-1) protein through the STAT-6 pathway polarizes the monocytes into alternatively activated (M2) macrophages with anti-inflammatory properties. By its transcriptional activity, it mediates the expression of arginase-1 (Arg1) and CD36. Arginine metabolism away from production of NO compromises the ability of infected macrophage to clear the intracellular pathogens.
It is certain that the overexpression of PGC-1 in skeletal muscle is leaky. Probably there is also an overexpression in macrophages priming them to M2
Mice transgenic for PGC-1 have massively elevated angiogenesis and higher capillary densities than control wild-type animals (Arany Z et al, Nature 2008 for PGC-1alpha and Rowe GC et al, Am J Physiol Endocrinol Metab 2011 for PGC-1beta). Therefore, there are much more blood and blood components (macrophages) in the muscles of those transgenic animals. Also there is more endothelial surface/volume available for the uptake of macrophages in those transgenic animals. This messes the whole thing even more up.
Finally, it has been demonstrated years ago (Yakeu et al, Atherosclerosis 2010) that PGC-1alpha and PGC-1beta mediate PPARγ/PGC-1α/β-driven macrophage M2 polarisation. M2 macrophages are more anti-inflammatory. PGC-1α and PGC-1β on the other hand were shown to downregulate pro-inflammatory M1 markers. Moreover, plasma levels of Th2 cytokines increased when PGC-1 was high, while those of Th1 cytokines decreased. Thus, PGC-1 may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARγ.
Already in 2006 Vats, D et al Cell Metabolism has shown that PGC-1 and oxidative metabolism promote M2 polarization of macrophages. They published that expression of PGC-1 primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response.
A more recent publication by Chan MM, PPAR Res, 2012 showed that PPAR gamma coactivator-1 (PGC-1) protein through the STAT-6 pathway polarizes the monocytes into alternatively activated (M2) macrophages with anti-inflammatory properties. By its transcriptional activity, it mediates the expression of arginase-1 (Arg1) and CD36. Arginine metabolism away from production of NO compromises the ability of infected macrophage to clear the intracellular pathogens.
It is certain that the overexpression of PGC-1 in skeletal muscle is leaky. Probably there is also an overexpression in macrophages priming them to M2
