Ok so hypertrophy is incredibly complicated and as gene's article shows for every increase in a system there is a compensatory measure.
But I figured this might be a fun exercise.
If you break hpertrophy down from the big picture there are basicaly three things that matter.
1. muscle protein synthesis.
2. myoblast fusion.
3. myoblast formation from stem cells.
So the question is which of the big three is rate limiting and in what scenarios.
We can actually identify one without pure hypothesis. Specifically, 2-3 seem to be rate limiting in the elderly.
the more interesting and contraversial question is which of the three is rate limiting in younger exercise trained individuals.
Full Version: Disecting Hypertrophy
Part 1 is a problem too, as a byproduct of steps 2/3. The elderly begin to show signs of insulin resistance and higher protein intake doesn't affect their myofibrillar protein synthesis rates like it does in the young.
Molecularly speaking, the limiting step is the speed of actin/myosin heavy chain mRNA translation in muscle, despite there being abundance of ribosomes. The limiting step to translation, if no one remembers their bio 101 or read my article, is the initiation step. That's why there is sometimes a fuss about inititation factors and all that shit. mTOR basically kicks off the signals that accelerate this process. Upstream of that, autocrine/paracrine IGF-I is the master control applying all the pressure. Of course, satellite cell proliferation is the "big picture" limiting step.
Molecularly speaking, the limiting step is the speed of actin/myosin heavy chain mRNA translation in muscle, despite there being abundance of ribosomes. The limiting step to translation, if no one remembers their bio 101 or read my article, is the initiation step. That's why there is sometimes a fuss about inititation factors and all that shit. mTOR basically kicks off the signals that accelerate this process. Upstream of that, autocrine/paracrine IGF-I is the master control applying all the pressure. Of course, satellite cell proliferation is the "big picture" limiting step.
My pet theory, unsubstantiated by any research I have seen, is that (3) is the limiting factor not only in the elderly, but in young persons as well. As I reported in the last issue of M&M, one model of hypertrophy is that androgens drive mesenchymal stem cells towards a myogenic lineage. Studies have shown that mesenchymal stem cells only have limited replicative capacity because they lack telomerase (1). Satellite cell fusion is crucial to hypertrophy, and if the pool of precursors to satellite cells is limited by a finite capacity for multipication, then bodybuilders, especially AAS using ones, will eventually exhaust the reservoir of stem cells required for continuing hypertrophy. In a sense, it is as if bodybuilders age prematurely since in non trained individuals there is much less demand for additional satellite cells.
(1) Bone Marrow Transplant. 2003 Nov;32(9):947-52.
Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.
Lee JJ, Nam CE, Kook H, Maciejewski JP, Kim YK, Chung IJ, Park KS, Lee IK, Hwang TJ, Kim HJ
(1) Bone Marrow Transplant. 2003 Nov;32(9):947-52.
Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.
Lee JJ, Nam CE, Kook H, Maciejewski JP, Kim YK, Chung IJ, Park KS, Lee IK, Hwang TJ, Kim HJ
Would repeated cycles of muscle gain/muscle loss speed this process even more, Nandi?
I have gone from 220 down to 165 several times, losing massive amounts of muscle mass only to rebuild. It's always extremely easy to pack it back on, but do you think this overly taxing to this reservoir of satellite cells?
I have gone from 220 down to 165 several times, losing massive amounts of muscle mass only to rebuild. It's always extremely easy to pack it back on, but do you think this overly taxing to this reservoir of satellite cells?
If my theory has any merit, it seems like repeated bouts of muscle loss and gain would tax the satellite cell precursor pool more than simply maintaining mass at a given level. I honestly don't know since my theory is only speculative. Maybe with your ease of regaining mass you are the counterexample that disproves my theory.
It would be interesting to compare average muscle cell telomere length in someone who has gone through repeated bouts of muscle loss/gain to an average person, or a bodybuilder who has maintained a relatively stable muscle mass. The shorter the telomere, the "older" the cell, in the sense that it has derived from a satellite cell that is the end result of many replications of precursor cells. Of course, once the telomeres of the stem cell population reach a certain shortness (they shorten with each division) they lose the ability to replicate further.
I wish I had your ability to gain so easily D Sade. I have to really struggle to keep it on. Perhaps age is one factor.
It would be interesting to compare average muscle cell telomere length in someone who has gone through repeated bouts of muscle loss/gain to an average person, or a bodybuilder who has maintained a relatively stable muscle mass. The shorter the telomere, the "older" the cell, in the sense that it has derived from a satellite cell that is the end result of many replications of precursor cells. Of course, once the telomeres of the stem cell population reach a certain shortness (they shorten with each division) they lose the ability to replicate further.
I wish I had your ability to gain so easily D Sade. I have to really struggle to keep it on. Perhaps age is one factor.
QUOTE(nandi12 @ Jul 4 2004, 12:11 AM)
It would be interesting to compare average muscle cell telomere length in someone who has gone through repeated bouts of muscle loss/gain to an average person, or a bodybuilder who has maintained a relatively stable muscle mass. The shorter the telomere, the "older" the cell, in the sense that it has derived from a satellite cell that is the end result of many replications of precursor cells. Of course, once the telomeres of the stem cell population reach a certain shortness (they shorten with each division) they lose the ability to replicate further.
Hayflick limit (the number of replications before telomere length goes to zero) has been shown not to be the limiting factor for many types of cell division.
As it turns out, telomeres are regenerated. The enzyme that aids in lengthening telomere is, surprise surprise, called telomerase.
Yes, that's the point virtualcyber. Normal cells (e.g, satellite cells, mensenchymal stem cells for the purpose of this discussion) either lack telomerase, or it is inactive, and can divide only a finite number of times. Telomerase is the hallmark of immortalized cells, like cancer. (Germline cells are the exception: they too possess telomerase)
D Sade, you got me thinking and I did a medline search and came up with this abstract. I wonder if in the athletes with FAMS stem cells are for some reason unable to replace the satelite cells which have exceeded their capacity to regenerate, or the athletes have depleted their stem cell supply so they can no longer generate new satellite cellls.
Med Sci Sports Exerc. 2003 Sep;35(9):1524-8.
Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres.
Collins M, Renault V, Grobler LA, St Clair Gibson A, Lambert MI, Wayne Derman E, Butler-Browne GS, Noakes TD, Mouly V.
Department of Human Biology, University of Cape Town, South Africa. mcollins@sports.uct.ac.za
INTRODUCTION/PURPOSE: Although the beneficial health effects of regular moderate exercise are well established, there is substantial evidence that the heavy training and racing carried out by endurance athletes can cause skeletal muscle damage. This damage is repaired by satellite cells that can undergo a finite number of cell divisions. In this study, we have compared a marker of skeletal muscle regeneration of athletes with exercise-associated chronic fatigue, a condition labeled the "fatigued athlete myopathic syndrome" (FAMS), with healthy asymptomatic age- and mileage-matched control endurance athletes. METHODS: Muscle biopsies of the vastus lateralis were obtained from 13 patients diagnosed with FAMS and from 13 healthy control subjects. DNA was extracted from the muscle samples and their telomeric restriction fragment (TRF) or telomere lengths were measured by Southern blot analysis. RESULTS: All 13 symptomatic athletes reported a progressive decline in athletic performance, decreased ability to tolerate high mileage training, and excessive muscular fatigue during exercise. The minimum value of TRF lengths (4.0 +/- 1.8 kb) measured on the DNA from vastus lateralis biopsies from these athletes were significantly shorter than those from 13 age- and mileage-matched control athletes (5.4 +/- 0.6 kb, P < 0.05). Three of the FAMS patients had extremely short telomeres (1.0 +/- 0.3 kb). The minimum TRF lengths of the remaining 10 symptomatic athletes (4.9 +/- 0.5 kb, P < 0.05) were also significantly shorter that those of the control athletes. CONCLUSION: These findings suggest that skeletal muscle from symptomatic athletes with FAMS show extensive regeneration which most probably results from more frequent bouts of satellite cell proliferation in response to recurrent training- and racing-induced muscle injury.
D Sade, you got me thinking and I did a medline search and came up with this abstract. I wonder if in the athletes with FAMS stem cells are for some reason unable to replace the satelite cells which have exceeded their capacity to regenerate, or the athletes have depleted their stem cell supply so they can no longer generate new satellite cellls.
Med Sci Sports Exerc. 2003 Sep;35(9):1524-8.
Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres.
Collins M, Renault V, Grobler LA, St Clair Gibson A, Lambert MI, Wayne Derman E, Butler-Browne GS, Noakes TD, Mouly V.
Department of Human Biology, University of Cape Town, South Africa. mcollins@sports.uct.ac.za
INTRODUCTION/PURPOSE: Although the beneficial health effects of regular moderate exercise are well established, there is substantial evidence that the heavy training and racing carried out by endurance athletes can cause skeletal muscle damage. This damage is repaired by satellite cells that can undergo a finite number of cell divisions. In this study, we have compared a marker of skeletal muscle regeneration of athletes with exercise-associated chronic fatigue, a condition labeled the "fatigued athlete myopathic syndrome" (FAMS), with healthy asymptomatic age- and mileage-matched control endurance athletes. METHODS: Muscle biopsies of the vastus lateralis were obtained from 13 patients diagnosed with FAMS and from 13 healthy control subjects. DNA was extracted from the muscle samples and their telomeric restriction fragment (TRF) or telomere lengths were measured by Southern blot analysis. RESULTS: All 13 symptomatic athletes reported a progressive decline in athletic performance, decreased ability to tolerate high mileage training, and excessive muscular fatigue during exercise. The minimum value of TRF lengths (4.0 +/- 1.8 kb) measured on the DNA from vastus lateralis biopsies from these athletes were significantly shorter than those from 13 age- and mileage-matched control athletes (5.4 +/- 0.6 kb, P < 0.05). Three of the FAMS patients had extremely short telomeres (1.0 +/- 0.3 kb). The minimum TRF lengths of the remaining 10 symptomatic athletes (4.9 +/- 0.5 kb, P < 0.05) were also significantly shorter that those of the control athletes. CONCLUSION: These findings suggest that skeletal muscle from symptomatic athletes with FAMS show extensive regeneration which most probably results from more frequent bouts of satellite cell proliferation in response to recurrent training- and racing-induced muscle injury.
God I love you guys 
This is why this board is so great.
So then lets introduce another variable in to the mix.
If we accept that (3) is rate limiting. Why is it that fast twitch fibers expirience much greater hypertrophy when trained than slow twitch fibers. Explained in the context of the big three above. Carefull now, because don't forget that deletion of calcinurin prevents fiber type switching but does not abolish hypertrophy.
What I am saying is that if #3 is rate limiting why do certain fibers hypertrophy at a greater rate than other fiber types. After all if its just the pool of myoblasts that limits growth would we not see even distrobution?
This is why this board is so great.So then lets introduce another variable in to the mix.
If we accept that (3) is rate limiting. Why is it that fast twitch fibers expirience much greater hypertrophy when trained than slow twitch fibers. Explained in the context of the big three above. Carefull now, because don't forget that deletion of calcinurin prevents fiber type switching but does not abolish hypertrophy.
What I am saying is that if #3 is rate limiting why do certain fibers hypertrophy at a greater rate than other fiber types. After all if its just the pool of myoblasts that limits growth would we not see even distrobution?
Good question, Spook. Just speaking in general terms (without identifying specific factors) I would guess that the fiber types more susceptible to hypertrophy are more readiy able to express the growth factors that are required to recruit satellite cells. Nevertheless, in the context of (3) it's ultimately the finite availability of satellite cells that limits the growth of all fiber types.
mTOR phosphorylation occuring preferentially in type II muscle has been proposed as one reason that fiber type grows more easily: "Fiber type-dependent mTOR phosphorylation may be a molecular basis by which some fiber types are more susceptible to contraction-induced hypertrophy"(1). However, this pathway may contribute to an increase in contractile protein, but a hallmark of skeletal muscle is the maintenance of a constant nuclear to cytoplasmic ratio. Since mature myocytes can't divide, the satellite cells donate the nuclei. So satellite cell availability again seems crucial.
(1) Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1086-90. Epub 2003 Jul 24.
Differential activation of mTOR signaling by contractile activity in skeletal muscle.
Parkington JD, Siebert AP, LeBrasseur NK, Fielding RA.
mTOR phosphorylation occuring preferentially in type II muscle has been proposed as one reason that fiber type grows more easily: "Fiber type-dependent mTOR phosphorylation may be a molecular basis by which some fiber types are more susceptible to contraction-induced hypertrophy"(1). However, this pathway may contribute to an increase in contractile protein, but a hallmark of skeletal muscle is the maintenance of a constant nuclear to cytoplasmic ratio. Since mature myocytes can't divide, the satellite cells donate the nuclei. So satellite cell availability again seems crucial.
(1) Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1086-90. Epub 2003 Jul 24.
Differential activation of mTOR signaling by contractile activity in skeletal muscle.
Parkington JD, Siebert AP, LeBrasseur NK, Fielding RA.
QUOTE
I'm talking off the top of my head here, just throwing out ideas.
that was the whole point of this thread.Anyway, see this is why I have a problem with (3). I agree that it would seem the most elegant solution but there are several things that make me uneasy about it.
The bigest of witch is fibertype differences. fast twitch do display more myogenein and follistation compared to slow twitch, BUT the primary protein responsible for myblast fusion is NFATC which is a calcinurin mediated peptide. This peptide is produced in a much greater abundance in slow twitch, and its imbplicated in fast to slow conversion as it upregulastes slow twitch myosin. So here we have a connundrum. fast twitch hypertrophy more but it would appear that slow twitch are the ones that actually atempt myoblast fusion more often.
This would be inline with the research on creatine. As I wrote in my phenogen writeup creatine apears to work allmost exclusively on slow twitch fibers. biopsies of fast twitch show no increase in creatine content from supplementation above baseline. Now creatine is also known to increase myoblast fusion, particularly in the elderly (10% in one study). Studies of uremea show an altered musculature with changes towards the "fast" myosins. However creatine administration normalizes this effect and and prevents switching of the soleus to a more "fast twitch" muscle.
So this makes me ask yet again what is rate limiting for fast twitch hypertrophy. As it dose not seem to be regulated by myoblast fusion or availability.
So what does fast twitch have that slow twitch dosen't? Well for one it seems MRF4, MyoD, and myogenin have a promotor region in fast twitch fibers that slow twitch lack. more interestingly is that even if alterations in MHC isoform are induced, by say fast to slow, this promotor region still exists. So it would seem that certain muscle fibers are designed to grow while others are not.
Also not to throw to much of a wrnech in the works but I don't think we can forget about the fact that it is perdominantly the fast twitch fibers that atrophy and undergo apoptosis in the geriatric. So whats rate limiting in the geriatric would more than likely differ from those of young individuals.
just some food for thought on my assumptions above.
QUOTE
Am J Physiol Cell Physiol. 2000 Sep;279(3):C682-90. Related Articles, Links
Satellite cell proliferation in low frequency-stimulated fast muscle of hypothyroid rat.
Putman CT, Dusterhoft S, Pette D.
Faculty of Biology, University of Konstanz, D-78457 Konstanz, Germany. tputman@per.ualberta.ca
Satellite cell proliferation was assessed in low-frequency-stimulated hypothyroid rat fast-twitch muscle by 5-bromo-2'-deoxyuridine (BrdU) labeling and subsequent staining of labeled muscle nuclei, and by staining for proliferating cell nuclear antigen (PCNA). BrdU labeling and PCNA staining were highly correlated and increased approximately fourfold at 5 days of stimulation, decayed thereafter, but remained elevated over control in 10- and 20-day stimulated muscles. Myogenin mRNA was approximately 4-fold elevated at 5 days and 1.5-fold at 10 days. Staining for myogenin protein yielded results similar to that for PCNA and BrdU. Furthermore, a detailed examination of the pattern of myogenin staining revealed that the number of myogenin-positive nuclei was elevated in the fast pure IIB fiber population at 5 and 10 days of chronic low-frequency stimulation. By 20 days, myogenin staining was observed in transforming fast fibers that coexpressed embryonic and adult myosin heavy chain isoforms. In the slower fiber populations (i.e., IIA and I), myogenin-positive transforming fibers that coexpressed embryonic myosin heavy chain, appeared already at 5 days. Thus the satellite cell progeny on slower fibers seemed to proliferate less and to fuse earlier to their associated fibers than the satellite cell progeny on fast fibers. We suggest that the increase in muscle nuclei of the fast fibers might be a prerequisite for fast-to-slow fiber type transitions.
PMID: 10942718 [PubMed - indexed for MEDLINE]
Satellite cell proliferation in low frequency-stimulated fast muscle of hypothyroid rat.
Putman CT, Dusterhoft S, Pette D.
Faculty of Biology, University of Konstanz, D-78457 Konstanz, Germany. tputman@per.ualberta.ca
Satellite cell proliferation was assessed in low-frequency-stimulated hypothyroid rat fast-twitch muscle by 5-bromo-2'-deoxyuridine (BrdU) labeling and subsequent staining of labeled muscle nuclei, and by staining for proliferating cell nuclear antigen (PCNA). BrdU labeling and PCNA staining were highly correlated and increased approximately fourfold at 5 days of stimulation, decayed thereafter, but remained elevated over control in 10- and 20-day stimulated muscles. Myogenin mRNA was approximately 4-fold elevated at 5 days and 1.5-fold at 10 days. Staining for myogenin protein yielded results similar to that for PCNA and BrdU. Furthermore, a detailed examination of the pattern of myogenin staining revealed that the number of myogenin-positive nuclei was elevated in the fast pure IIB fiber population at 5 and 10 days of chronic low-frequency stimulation. By 20 days, myogenin staining was observed in transforming fast fibers that coexpressed embryonic and adult myosin heavy chain isoforms. In the slower fiber populations (i.e., IIA and I), myogenin-positive transforming fibers that coexpressed embryonic myosin heavy chain, appeared already at 5 days. Thus the satellite cell progeny on slower fibers seemed to proliferate less and to fuse earlier to their associated fibers than the satellite cell progeny on fast fibers. We suggest that the increase in muscle nuclei of the fast fibers might be a prerequisite for fast-to-slow fiber type transitions.
PMID: 10942718 [PubMed - indexed for MEDLINE]
here is a nice study that backs up your reasoning nandi.
QUOTE
Am J Physiol Cell Physiol. 2002 Oct;283(4):C1228-41. Related Articles, Links
Aging-related satellite cell differentiation defect occurs prematurely after Ski-induced muscle hypertrophy.
Charge SB, Brack AS, Hughes SM.
Medical Research Council (MRC) Muscle and Cell Motility Unit, MRC Centre for Developmental Neurobiology, Guy's Campus, King's College London, London SE1 1UL, UK.
To investigate the cause of skeletal muscle weakening during aging we examined the sequence of cellular changes in murine muscles. Satellite cells isolated from single muscle fibers terminally differentiate progressively less well with increasing age of donor. This change is detected before decline in satellite cell numbers and all histological changes examined here. In MSVski transgenic mice, which show type IIb fiber hypertrophy, initial muscle weakness is followed by muscle degeneration in the first year of life. This degeneration is accompanied by a spectrum of changes typical of normal muscle aging and a more marked decline in satellite cell differentiation efficiency. On a myoD-null genetic background, in which satellite cell differentiation is defective, the MSVski muscle phenotype is aggravated. This suggests that, on a wild-type genetic background, satellite cells are capable of repairing MSVski fibers and preserving muscle integrity in early life. We propose that decline in myogenic cell differentiation efficiency is an early event in aging-related loss of muscle function, both in normal aging and in some late-onset muscle degenerative conditions.
PMID: 12225986 [PubMed - indexed for MEDLINE]
Aging-related satellite cell differentiation defect occurs prematurely after Ski-induced muscle hypertrophy.
Charge SB, Brack AS, Hughes SM.
Medical Research Council (MRC) Muscle and Cell Motility Unit, MRC Centre for Developmental Neurobiology, Guy's Campus, King's College London, London SE1 1UL, UK.
To investigate the cause of skeletal muscle weakening during aging we examined the sequence of cellular changes in murine muscles. Satellite cells isolated from single muscle fibers terminally differentiate progressively less well with increasing age of donor. This change is detected before decline in satellite cell numbers and all histological changes examined here. In MSVski transgenic mice, which show type IIb fiber hypertrophy, initial muscle weakness is followed by muscle degeneration in the first year of life. This degeneration is accompanied by a spectrum of changes typical of normal muscle aging and a more marked decline in satellite cell differentiation efficiency. On a myoD-null genetic background, in which satellite cell differentiation is defective, the MSVski muscle phenotype is aggravated. This suggests that, on a wild-type genetic background, satellite cells are capable of repairing MSVski fibers and preserving muscle integrity in early life. We propose that decline in myogenic cell differentiation efficiency is an early event in aging-related loss of muscle function, both in normal aging and in some late-onset muscle degenerative conditions.
PMID: 12225986 [PubMed - indexed for MEDLINE]
When I mentioned growth factors earlier one I had in mind was MGF. This is known to activate satellite cells and declines with aging, along with the preferential decline in type II fibers you mentioned earlier. This is one thing that made me think that type II fibers might be preferentially recruiting and activating satellite cells. But you seem to have presented some good evidence that it is the type I fibers that more readily attract satellite cells. I seem to recall reading that MGF was expressed primariliy in type II fibers, but I will have to check.
Yeah I think MGF explains alot of it.
Here is my take as far as I understand things.
Slow twitch fibers "want" to undergo myoblast fusion much more than Fast twitch. But slow witch is limited by the availability of satallite cells. Fast twitch dosen't atempt fusion as much as slow twitch but has much greater proliferation of sattalie cells creating a larger pool.
The things that I am still have not integrated in to my model of hypertrophy is the sharp differences in the slow twitch derived satalite cells vs. the fast twitch derived satalite cells. From what I can tell they have different mechanisms for recurtment. For example they express different forms of the Fibroblast regulator factor receptors (FRP). So it apears that maybe the signals for release of satalite cells from the different muscle types might differ? And if thats ture maybe its the fact that exercise produces what ever releases fast twitch satalite cells while slow twitch derived cells do not respond to this stimulus.
Either way it does look like whats rate limiting for the different fiber types does differ. Man I wish Labrat was here. I bet she would have something to say on the matter.
Here is my take as far as I understand things.
Slow twitch fibers "want" to undergo myoblast fusion much more than Fast twitch. But slow witch is limited by the availability of satallite cells. Fast twitch dosen't atempt fusion as much as slow twitch but has much greater proliferation of sattalie cells creating a larger pool.
The things that I am still have not integrated in to my model of hypertrophy is the sharp differences in the slow twitch derived satalite cells vs. the fast twitch derived satalite cells. From what I can tell they have different mechanisms for recurtment. For example they express different forms of the Fibroblast regulator factor receptors (FRP). So it apears that maybe the signals for release of satalite cells from the different muscle types might differ? And if thats ture maybe its the fact that exercise produces what ever releases fast twitch satalite cells while slow twitch derived cells do not respond to this stimulus.
Either way it does look like whats rate limiting for the different fiber types does differ. Man I wish Labrat was here. I bet she would have something to say on the matter.
I think this is essentially the same question you are askig Spook, but one thing that puzzles me as well is if all satellite cells are derived from the same pluripotent stem cells, what factors are being secreted by the myocyte to which the satellite cells fuse that switch on the genes in the satellite cells that determine whether they become fast twitch or slow twitch?
Most of this discussion is WAY over my head. However, this abstract seems to suggest that Calcineurin is something to focus on in regards to the question below...(Then again, I may be completely off-base here, but it is fascinating to study nonetheless)...
"this makes me ask yet again what is rate limiting for fast twitch hypertrophy. As it dose not seem to be regulated by myoblast fusion or availability."
Am J Physiol Cell Physiol. 2002 May;282(5):C984-92. Related Articles, Links
Calcineurin differentially regulates maintenance and growth of phenotypically distinct muscles.
Mitchell PO, Mills ST, Pavlath GK.
Department of Pharmacology and Graduate Program in Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322, USA.
Adequate muscle mass is critical for human health. The molecular pathways regulating maintenance and growth of adult skeletal muscle are little understood. Calcineurin (CN) is implicated as a key signaling molecule in hypertrophy. Whether CN is involved in all forms of muscle growth or in different muscles is unknown. Here, we examine the role of CN in regulating maintenance of muscle size and growth of atrophied muscle in the soleus (slow) and plantaris (fast). The CN inhibitor cyclosporin A (CsA) differentially affects muscle growth and maintenance depending on muscle phenotype. The plantaris is more severely affected by CsA than the soleus in both growth conditions. One-week vs. 2-wk CsA treatment suggests that both CN-dependent and CN-independent growth occur in the atrophied soleus, whereas plantaris growth appears to be totally CN dependent. Our results suggest that CN regulates multiple types of muscle growth, depending both on muscle phenotype and stage of myofiber growth. Differential expression of components of the CN pathway occurs and may contribute to the differences between muscles.
"this makes me ask yet again what is rate limiting for fast twitch hypertrophy. As it dose not seem to be regulated by myoblast fusion or availability."
Am J Physiol Cell Physiol. 2002 May;282(5):C984-92. Related Articles, Links
Calcineurin differentially regulates maintenance and growth of phenotypically distinct muscles.
Mitchell PO, Mills ST, Pavlath GK.
Department of Pharmacology and Graduate Program in Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322, USA.
Adequate muscle mass is critical for human health. The molecular pathways regulating maintenance and growth of adult skeletal muscle are little understood. Calcineurin (CN) is implicated as a key signaling molecule in hypertrophy. Whether CN is involved in all forms of muscle growth or in different muscles is unknown. Here, we examine the role of CN in regulating maintenance of muscle size and growth of atrophied muscle in the soleus (slow) and plantaris (fast). The CN inhibitor cyclosporin A (CsA) differentially affects muscle growth and maintenance depending on muscle phenotype. The plantaris is more severely affected by CsA than the soleus in both growth conditions. One-week vs. 2-wk CsA treatment suggests that both CN-dependent and CN-independent growth occur in the atrophied soleus, whereas plantaris growth appears to be totally CN dependent. Our results suggest that CN regulates multiple types of muscle growth, depending both on muscle phenotype and stage of myofiber growth. Differential expression of components of the CN pathway occurs and may contribute to the differences between muscles.
QUOTE
I think this is essentially the same question you are askig Spook, but one thing that puzzles me as well is if all satellite cells are derived from the same pluripotent stem cells, what factors are being secreted by the myocyte to which the satellite cells fuse that switch on the genes in the satellite cells that determine whether they become fast twitch or slow twitch?
well if you go by the following study then they don't in humans. Which makes this whole discussion totaly pointless. I am not so convinced that just because they express both fast and slow isoforms that mens they are the same. For example similar behavior has been seen in rodents. Grafts of slow sattalite cells were attached to the EDL and found that they expressed a very similar MHC isoform pattern of the EDL but it was still not totaly identical. So I guess I don't agree with the strength of the wording in the study below.
QUOTE
Neuromuscul Disord. 2001 Nov;11(8):747-52. Related Articles, Links
A discrepancy resolved: human satellite cells are not preprogrammed to fast and slow lineages.
Bonavaud S, Agbulut O, Nizard R, D'honneur G, Mouly V, Butler-Browne G.
CNRS UMR 7000, Faculte de Medecine Pitie-Salpetriere, 105 boulevard de l'Hopital, F-75634 Paris cedex 13, France.
Satellite cells from chicken and mouse muscle when differentiated in vitro have been shown to display a myosin heavy chain phenotype that corresponds to the fibre from which they originated. Indirect evidence has suggested that this might not be the case for human satellite cells. In the present study we have compared the myosin heavy chain (MHC) profile expressed by differentiated cultures of satellite cells isolated from single fast or slow muscle fibres. The MHC composition of the isolated fibres was determined by sodium dodecyl sulfate glycerol gel electrophoresis and Western blotting. The MHC profile expressed by the differentiated myotubes was identified by immunostaining using specific antibodies. Our results show that all human satellite cells isolated from either fast or slow fibres form myotubes in vitro which co-express both fast and slow MHCs independently of the fibre type from which they originated. These results confirm that human satellite cells, in contrast to those of birds and rodents, are not confined to distinct fast and slow lineages.
PMID: 11595517 [PubMed - indexed for MEDLINE]
A discrepancy resolved: human satellite cells are not preprogrammed to fast and slow lineages.
Bonavaud S, Agbulut O, Nizard R, D'honneur G, Mouly V, Butler-Browne G.
CNRS UMR 7000, Faculte de Medecine Pitie-Salpetriere, 105 boulevard de l'Hopital, F-75634 Paris cedex 13, France.
Satellite cells from chicken and mouse muscle when differentiated in vitro have been shown to display a myosin heavy chain phenotype that corresponds to the fibre from which they originated. Indirect evidence has suggested that this might not be the case for human satellite cells. In the present study we have compared the myosin heavy chain (MHC) profile expressed by differentiated cultures of satellite cells isolated from single fast or slow muscle fibres. The MHC composition of the isolated fibres was determined by sodium dodecyl sulfate glycerol gel electrophoresis and Western blotting. The MHC profile expressed by the differentiated myotubes was identified by immunostaining using specific antibodies. Our results show that all human satellite cells isolated from either fast or slow fibres form myotubes in vitro which co-express both fast and slow MHCs independently of the fibre type from which they originated. These results confirm that human satellite cells, in contrast to those of birds and rodents, are not confined to distinct fast and slow lineages.
PMID: 11595517 [PubMed - indexed for MEDLINE]
1: Acta Neuropathol (Berl). 2004 Jun 24 [Epub ahead of print] Related Articles, Links
Marked reduction of focal adhesion kinase, serum response factor and myocyte enhancer factor 2C, but increase in RhoA and myostatin in the hindlimb dy mouse muscles.
Sakuma K, Nakao R, Inashima S, Hirata M, Kubo T, Yasuhara M.
Department of Legal Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan.
Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration. This is probably due to decreased formation of multi nucleated myotubes resulting from a myoblast fusion defect. When receiving a mechanical signal from muscle membranes, a cascade of RhoA, focal adhesion kinase (FAK), and serum response factor (SRF) positively regulates myogenesis and muscle hypertrophy associated with functional overload. In contrast, myostatin, a potent negative regulator of skeletal muscle hypertrophy, appears to be up-regulated in the muscles of mdx mice, an animal model for Duchenne muscular dystrophy. Using Western blot and immunohistochemical analyses, we investigated the levels of RhoA, FAK, SRF, and myostatin in the skeletal muscles of dy mice. The amount of RhoA protein was increased in the hindlimb muscles of dy mice aged 12 weeks. At 12 weeks, FAK immunoreactivity was observed in the myonuclei and/or satellite cells of normal mice, but not of dy mice. SRF protein levels decreased markedly in the gastrocnemius and rectus femoris muscles of dy mice at 2 and 12 weeks. Several muscle fibers in normal mice possessed uniform SRF immunoreactivity in the cytoplasm. An SRF immunostaining pattern in muscle was not detected in dy mice. Western blot and the densitometric analysis showed a decreased amount of myocyte enhancer factor 2C (MEF2C) in hindlimb muscles of dy mice. Although slight myostatin immunoreactivity was observed in the nuclei of some normal mice, marked myostatin immunoreactivity was observed in the cytoplasm of mature dy mice myonuclei and/or satellite cells. A low expression of FAK, SRF and MEF2C in muscles of dy mice may inhibit postnatal muscle hypertrophy by fusing satellite cells with existing fibers. Enhancing myostatin protein would result in further atrophy and degeneration of muscle fiber in dy mice.
PMID: 15221330 [PubMed - as supplied by publisher]
No talk of fiber-type differences, but I have also not heard of MEF2C, FAK, and SRF before. I need to grab the full text of this new study.
Marked reduction of focal adhesion kinase, serum response factor and myocyte enhancer factor 2C, but increase in RhoA and myostatin in the hindlimb dy mouse muscles.
Sakuma K, Nakao R, Inashima S, Hirata M, Kubo T, Yasuhara M.
Department of Legal Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan.
Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration. This is probably due to decreased formation of multi nucleated myotubes resulting from a myoblast fusion defect. When receiving a mechanical signal from muscle membranes, a cascade of RhoA, focal adhesion kinase (FAK), and serum response factor (SRF) positively regulates myogenesis and muscle hypertrophy associated with functional overload. In contrast, myostatin, a potent negative regulator of skeletal muscle hypertrophy, appears to be up-regulated in the muscles of mdx mice, an animal model for Duchenne muscular dystrophy. Using Western blot and immunohistochemical analyses, we investigated the levels of RhoA, FAK, SRF, and myostatin in the skeletal muscles of dy mice. The amount of RhoA protein was increased in the hindlimb muscles of dy mice aged 12 weeks. At 12 weeks, FAK immunoreactivity was observed in the myonuclei and/or satellite cells of normal mice, but not of dy mice. SRF protein levels decreased markedly in the gastrocnemius and rectus femoris muscles of dy mice at 2 and 12 weeks. Several muscle fibers in normal mice possessed uniform SRF immunoreactivity in the cytoplasm. An SRF immunostaining pattern in muscle was not detected in dy mice. Western blot and the densitometric analysis showed a decreased amount of myocyte enhancer factor 2C (MEF2C) in hindlimb muscles of dy mice. Although slight myostatin immunoreactivity was observed in the nuclei of some normal mice, marked myostatin immunoreactivity was observed in the cytoplasm of mature dy mice myonuclei and/or satellite cells. A low expression of FAK, SRF and MEF2C in muscles of dy mice may inhibit postnatal muscle hypertrophy by fusing satellite cells with existing fibers. Enhancing myostatin protein would result in further atrophy and degeneration of muscle fiber in dy mice.
PMID: 15221330 [PubMed - as supplied by publisher]
No talk of fiber-type differences, but I have also not heard of MEF2C, FAK, and SRF before. I need to grab the full text of this new study.
QUOTE
J Physiol. 2004 Feb 15;555(Pt 1):231-40. Epub 2003 Oct 17. Related Articles, Links
The effect of recombinant human growth hormone and resistance training on IGF-I mRNA expression in the muscles of elderly men.
Hameed M, Lange KH, Andersen JL, Schjerling P, Kjaer M, Harridge SD, Goldspink G.
Department of Surgery, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. m.hameed@rfc.ucl.ac.uk
The expression of two isoforms of insulin-like growth factor-I (IGF-I): mechano growth factor (MGF) and IGF-IEa were studied in muscle in response to growth hormone (GH) administration with and without resistance training in healthy elderly men. A third isoform, IGF-IEb was also investigated in response to resistance training only. The subjects (age 74 +/- 1 years, mean +/- S.E.M) were assigned to either resistance training with placebo, resistance training combined with GH administration or GH administration alone. Real-time quantitative RT-PCR was used to determine mRNA levels in biopsies from the vastus lateralis muscle at baseline, after 5 and 12 weeks in the three groups. GH administration did not change MGF mRNA at 5 weeks, but significantly increased IGF-IEa mRNA (237%). After 12 weeks, MGF mRNA was significantly increased (80%) compared to baseline. Five weeks of resistance training significantly increased the mRNA expression of MGF (163%), IGF-IEa (68%) and IGF-IEb (75%). No further changes were observed after 12 weeks. However, after 5 weeks of training combined with GH treatment, MGF mRNA increased significantly (456%) and IGF-IEa mRNA by (167%). No further significant changes were noted at 12 weeks. The data suggest that when mechanical loading in the form of resistance training is combined with GH, MGF mRNA levels are enhanced. This may reflect an overall up-regulation of transcription of the IGF-I gene prior to splicing.
PMID: 14565994 [PubMed - in process]
The effect of recombinant human growth hormone and resistance training on IGF-I mRNA expression in the muscles of elderly men.
Hameed M, Lange KH, Andersen JL, Schjerling P, Kjaer M, Harridge SD, Goldspink G.
Department of Surgery, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. m.hameed@rfc.ucl.ac.uk
The expression of two isoforms of insulin-like growth factor-I (IGF-I): mechano growth factor (MGF) and IGF-IEa were studied in muscle in response to growth hormone (GH) administration with and without resistance training in healthy elderly men. A third isoform, IGF-IEb was also investigated in response to resistance training only. The subjects (age 74 +/- 1 years, mean +/- S.E.M) were assigned to either resistance training with placebo, resistance training combined with GH administration or GH administration alone. Real-time quantitative RT-PCR was used to determine mRNA levels in biopsies from the vastus lateralis muscle at baseline, after 5 and 12 weeks in the three groups. GH administration did not change MGF mRNA at 5 weeks, but significantly increased IGF-IEa mRNA (237%). After 12 weeks, MGF mRNA was significantly increased (80%) compared to baseline. Five weeks of resistance training significantly increased the mRNA expression of MGF (163%), IGF-IEa (68%) and IGF-IEb (75%). No further changes were observed after 12 weeks. However, after 5 weeks of training combined with GH treatment, MGF mRNA increased significantly (456%) and IGF-IEa mRNA by (167%). No further significant changes were noted at 12 weeks. The data suggest that when mechanical loading in the form of resistance training is combined with GH, MGF mRNA levels are enhanced. This may reflect an overall up-regulation of transcription of the IGF-I gene prior to splicing.
PMID: 14565994 [PubMed - in process]
Not to complicate things further but MGF's importance might be overblown. if you look at this study training + GH wickedly increased MGF levels but as far as i know most peple think GH sucks as a muscle builder. Of course the median age was 74 so that could have had an impact as well.
I am seeing a lot of references to Notch-1 Delta ligands in muscle. Supposedly this researcher is proposing failure of up-regulation accounting for decreased abilities for muscle to regenerate and recover from injury with age.
1: Sci Aging Knowledge Environ. 2003 Dec 3;2003(48):pe34. Related Articles, Links
Does the road to muscle rejuvenation go through Notch?
Miller JB, Emerson CP Jr.
Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
The capacity of skeletal muscles to repair and regenerate declines during aging in humans, and this decline may lead to muscle loss and frailty. Conboy et al. show that injured muscles of aging mice are defective in Notch signaling, because up-regulation of the Notch ligand, Delta-1, is impaired. Delta-1 promotes proliferation of the satellite cells that repair damaged muscles, and Conboy et al. show that experimental activation of Notch signaling is sufficient to reverse the age-related decline in muscle regenerative capacity. Extension of these important findings to humans could lead to the development of new therapeutic approaches to maintain muscle function during aging.
Publication Types:
Review
Review, Tutorial
PMID: 14657508 [PubMed - indexed for MEDLINE]
Science. 2003 Nov 28;302(5650):1575-7. Related Articles, Links
Notch-mediated restoration of regenerative potential to aged muscle.
Conboy IM, Conboy MJ, Smythe GM, Rando TA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA.
A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
PMID: 14645852 [PubMed - indexed for MEDLINE]
1: Sci Aging Knowledge Environ. 2003 Dec 3;2003(48):pe34. Related Articles, Links
Does the road to muscle rejuvenation go through Notch?
Miller JB, Emerson CP Jr.
Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
The capacity of skeletal muscles to repair and regenerate declines during aging in humans, and this decline may lead to muscle loss and frailty. Conboy et al. show that injured muscles of aging mice are defective in Notch signaling, because up-regulation of the Notch ligand, Delta-1, is impaired. Delta-1 promotes proliferation of the satellite cells that repair damaged muscles, and Conboy et al. show that experimental activation of Notch signaling is sufficient to reverse the age-related decline in muscle regenerative capacity. Extension of these important findings to humans could lead to the development of new therapeutic approaches to maintain muscle function during aging.
Publication Types:
Review
Review, Tutorial
PMID: 14657508 [PubMed - indexed for MEDLINE]
Science. 2003 Nov 28;302(5650):1575-7. Related Articles, Links
Notch-mediated restoration of regenerative potential to aged muscle.
Conboy IM, Conboy MJ, Smythe GM, Rando TA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA.
A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
PMID: 14645852 [PubMed - indexed for MEDLINE]
QUOTE(nandi12 @ Jul 4 2004, 01:21 AM)
Yes, that's the point virtualcyber. Normal cells (e.g, satellite cells, mensenchymal stem cells for the purpose of this discussion) either lack telomerase, or it is inactive, and can divide only a finite number of times. Telomerase is the hallmark of immortalized cells, like cancer. (Germline cells are the exception: they too possess telomerase)
Perhaps I am mistaken, but from what I remember:
(1) satellite cells do express telomerase.
(2) The cells that normally has short telomeres will suddenly grow them (that is, the expression of telomerase will be activated by some mechanism)
Finally, I cannot remember where I got this, but telomerase expression is modulated by aging process.
-----------------
So, it seems to me that the stem cell availabilty/replication is unlikely to be the limiting factor. Also, given the adaptiveness of human bodies, it would not make much sense that muscles suddenly atrophy due to the lack of cells.
QUOTE
So, it seems to me that the stem cell availabilty/replication is unlikely to be the limiting factor. Also, given the adaptiveness of human bodies, it would not make much sense that muscles suddenly atrophy due to the lack of cells.
Actually it seems this is exactly what happens, in fast fibers anyway. It seems fast fibers even when not training are in need of constant repair. They generally undergo cell death during the geriatric years because of limited satallite cell pools can't repair damage so they enter programmed death.
Dsade, yeah notch 1 delta looked intriuging but from what I have seen in human studies that if anyting its not that important in humans. It does seem that there are sex differences as well in the aged. If I recall correctly from somme of the human research done it was mainly MyoD that was lower with age, compared to the other 4 big myogenic regulatory factors. From training though, I remember particularly in women it was p21 that did not respond. Normally training supresses this, but older women showed a particular defect in this aspect. old men did as well but not nearly as bad as women. But the question remains if any of this research is applicable to young trained atheletes.
Have a look at figure 1 here, virtualcyber:
http://mcr.aacrjournals.org/cgi/content/full/1/9/643
As you can see, satellite cells are capable of undergoing about 50 rounds of division, fairly characteristic of normal cells lacking telomerase. Perhaps you are thinking of numerous experiments where satellite cells have been transfected with the telomerase gene in an attempt to increase their proliferative capacity in the quest for treatments of wasting diseases.
http://mcr.aacrjournals.org/cgi/content/full/1/9/643
As you can see, satellite cells are capable of undergoing about 50 rounds of division, fairly characteristic of normal cells lacking telomerase. Perhaps you are thinking of numerous experiments where satellite cells have been transfected with the telomerase gene in an attempt to increase their proliferative capacity in the quest for treatments of wasting diseases.
QUOTE(nandi12 @ Jul 4 2004, 02:48 AM)
I think this is essentially the same question you are askig Spook, but one thing that puzzles me as well is if all satellite cells are derived from the same pluripotent stem cells, what factors are being secreted by the myocyte to which the satellite cells fuse that switch on the genes in the satellite cells that determine whether they become fast twitch or slow twitch?
Does this abstract answer any of the questions, or does it not apply at all? This is all out of my league but I am trying to brain-storm ideas/possibilities...
Mol Cell Biol. 2002 Sep;22(17):6199-208. Related Articles, Links
Identification of novel MyoD gene targets in proliferating myogenic stem cells.
Wyzykowski JC, Winata TI, Mitin N, Taparowsky EJ, Konieczny SF.
Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907-1392, USA.
A major control point for skeletal myogenesis revolves around the muscle basic helix-loop-helix gene family that includes MyoD, Myf-5, myogenin, and MRF4. Myogenin and MRF4 are thought to be essential to terminal differentiation events, whereas MyoD and Myf-5 are critical to establishing the myogenic cell lineage and producing committed, undifferentiated myogenic stem cells (myoblasts). Although mouse genetic studies have revealed the importance of MyoD and Myf-5 for myoblast development, the genetic targets of MyoD and Myf-5 activity in undifferentiated myoblasts remain unknown. In this study, we investigated the function of MyoD as a transcriptional activator in undifferentiated myoblasts. By using conditional expression of MyoD, in conjunction with suppression subtractive hybridizations, we show that the Id3 and NP1 (neuronal pentraxin 1) genes become transcriptionally active following MyoD induction in undifferentiated myoblasts. Activation of Id3 and NP1 represents a stable, heritable event that does not rely on continued MyoD activity and is not subject to negative regulation by an activated H-Ras G12V protein. These results are the first to demonstrate that MyoD functions as a transcriptional activator in myogenic stem cells and that this key myogenic regulatory factor exhibits different gene target specificities, depending upon the cellular environment.
PMID: 12167713 [PubMed - indexed for MEDLINE]
QUOTE
Also not to throw to much of a wrnech in the works but I don't think we can forget about the fact that it is perdominantly the fast twitch fibers that atrophy and undergo apoptosis in the geriatric. So whats rate limiting in the geriatric would more than likely differ from those of young individuals.
Apropos of your above comment, Spook, I found this interesting. Note that only fast twitch mucle is mentioned.
Arch Biochem Biophys. 2004 May 1;425(1):42-50. Related Articles, Links
Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging.
Cai D, Lee KK, Li M, Tang MK, Chan KM.
In this study, we have used two-dimensional electrophoresis, protein sequencing, immunoblotting, and immunohistochemistry to identify proteins that were differentially expressed during aging in human and rat skeletal muscles. Ubiquitin was identified. It was expressed at high levels in old fast-twitch muscles but at low levels in young fast-twitch muscles. It was also discovered that exogenous ubiquitin could suppress the growth of C2C12 cells, in vitro. The reduction in C2C12 cell growth was not attributed to an increase in apoptosis but to an inhibition in cell cycle entry. Furthermore, it was possible to induce muscles to degenerate in vivo by injecting a high dose of exogenous ubiquitin into young healthy skeletal muscles. These results suggest that hyperactivity of the ubiquitin-proteasome pathway is involved in the aging process of fast-twitch muscles. In addition, ubiquitin-dependent growth suppression in satellite cells may be associated with the poor healing potential of old skeletal muscles.
So is Ubiquitin active in any other tissues, and can it be suppressed?
The ubiquitin proteasome pathway of protein degradation is widespread throughout the body. It is one way the body degrades and disposes of proteins. Perhaps two of the best known inhibitors of this pathway of protein degradation are androgens and insulin. This almost certainly accounts for at least part of the anabolic/anticatabolic action of these compounds.
If you're interested, this is the best review I've come across on the topic:
http://physrev.physiology.org/cgi/content/...t/full/82/2/373
If you're interested, this is the best review I've come across on the topic:
http://physrev.physiology.org/cgi/content/...t/full/82/2/373
QUOTE(nandi12 @ Jul 4 2004, 01:20 PM)
Have a look at figure 1 here, virtualcyber:
http://mcr.aacrjournals.org/cgi/content/full/1/9/643
As you can see, satellite cells are capable of undergoing about 50 rounds of division, fairly characteristic of normal cells lacking telomerase. Perhaps you are thinking of numerous experiments where satellite cells have been transfected with the telomerase gene in an attempt to increase their proliferative capacity in the quest for treatments of wasting diseases.
http://mcr.aacrjournals.org/cgi/content/full/1/9/643
As you can see, satellite cells are capable of undergoing about 50 rounds of division, fairly characteristic of normal cells lacking telomerase. Perhaps you are thinking of numerous experiments where satellite cells have been transfected with the telomerase gene in an attempt to increase their proliferative capacity in the quest for treatments of wasting diseases.
The citation supports my position, not what you have proposed above.
Before getting more specific about the points I have raised, let me explain the general misconception about telomeres. Since the discovery of telomeres, people have long thought that it imposed the limit on how many times cells can divide. At macroscopic level, it was thought to place the upper limit on how long a multi-cellular organism can survive.
This belief turned out to be incorrect when it was discovered that certain cells whose telomeres became very short suddenly came to have fresh, long telomeres. That is, telomeres that became short upon repeated cell division, were regrown. More importantly, what was found was _NOT_ that there was constant telomerase activity that kept the cells telomere length long, but that telomerase was simply triggered upon certain environmental conditions.
Simply put, cells divide as much as they are needed. Telomere is not the real "bottleneck" of the proliferative life span, because it is regenerated upon demand.
Above you have point out that satellite cells can only divide certain number of times, in vitro. But I did not dispute that; yes, without regrowing telomeres, cells will stop replicating. But it has nothing to do with my general point, which is that telomerase activity kicks in upon demand. There is nothing in the paper that shows the satellite cells are the exception to this general rule.
Telomerase perhaps mediates satellite cell division/proliferation, given proper signals from another organ/tissue/whatever. Note that it is not a limitation in itself.
----------------------------------------------------
There are other reasons why I think your proposed view is unlikely to be correct one. Near the end of the paper you cited, it was explained, that:
QUOTE
We have shown previously that normal adult skeletal muscle satellite cells in vivo do not reach M1, even at old ages (44).
What the authors are saying is that the Hayflick limit is generally not reached. Now, granted, bb'ers are not averages dudes. Because bb'ers work out so much, perhaps it is possible that they are reaching the Hayflick limit? Even if it were true, however, there are two further problems with the theory that the telomere length is the limiting factor: first, the satelllite cells can divide even AFTER the Hayflick limit has been reached, even though it has an upper bound (called M2 in the paper). Secondly, the satellite cell division generally stops long before the Hayflick limit is reached. See the discussion section of the cited paper.
All these facts about telomeres may seem random. But they make more sense if one thinks of telomere as not the physical limit, but as a signal to stop replicating.
Let me put it another way: one cannot remove the bottleneck to muscle cell growth / increase by augmenting telomerase activity. Rather, one has to deal with the upstream signal modulates its activity.
QUOTE(nandi12 @ Jul 3 2004, 06:44 PM)
My pet theory, unsubstantiated by any research I have seen, is that (3) is the limiting factor not only in the elderly, but in young persons as well. As I reported in the last issue of M&M, one model of hypertrophy is that androgens drive mesenchymal stem cells towards a myogenic lineage. Studies have shown that mesenchymal stem cells only have limited replicative capacity because they lack telomerase (1). Satellite cell fusion is crucial to hypertrophy, and if the pool of precursors to satellite cells is limited by a finite capacity for multipication, then bodybuilders, especially AAS using ones, will eventually exhaust the reservoir of stem cells required for continuing hypertrophy. In a sense, it is as if bodybuilders age prematurely since in non trained individuals there is much less demand for additional satellite cells.
(1) Bone Marrow Transplant. 2003 Nov;32(9):947-52.
Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.
Lee JJ, Nam CE, Kook H, Maciejewski JP, Kim YK, Chung IJ, Park KS, Lee IK, Hwang TJ, Kim HJ
(1) Bone Marrow Transplant. 2003 Nov;32(9):947-52.
Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.
Lee JJ, Nam CE, Kook H, Maciejewski JP, Kim YK, Chung IJ, Park KS, Lee IK, Hwang TJ, Kim HJ
On that note, what of stem cell donation/transplantation -- would it help turn us into Christopher Reeves in that South Park episode??
Also, what of leukemias, where the subject has all of that destroyed via TBI, then replaced from a donor. Would you expect a much more finite number in such subjects? Or does this only destroy hemopoietic stem cells and not mesenchymal stem cells??
Well, in animals both satellite cells and stem cells have succussfully been transplanted into muscle tissue with a resulting increase in fiber size.
Satellite cells and mesenchymal stem cells are normally quiescent, and are thus much less subject to the lethal effects of radiation than are hematopoietic stem cells which are always rapidly dividing. Cells lining the intestines replace themselves rapidly as well, hence the diarrhea associated with radiation and/or chemotherapy.
Satellite cells and mesenchymal stem cells are normally quiescent, and are thus much less subject to the lethal effects of radiation than are hematopoietic stem cells which are always rapidly dividing. Cells lining the intestines replace themselves rapidly as well, hence the diarrhea associated with radiation and/or chemotherapy.
Jsut a bump for Nandi.
Looks like ATP might be one of the muscle->satalite cell signaling molecules.
Looks like ATP might be one of the muscle->satalite cell signaling molecules.
QUOTE
FASEB J. 2004 Jul 1 [Epub ahead of print] Related Articles, Links
Purinoceptor expression in regenerating skeletal muscle in the mdx mouse model of muscular dystrophy and in satellite cell cultures.
Ryten M, Yang SY, Dunn PM, Goldspink G, Burnstock G.
ATP is an important extracellular signaling molecule mediating its effects by activation of P2X and P2Y receptors. P2 receptors are expressed during muscle development, and recent findings demonstrate that ATP can regulate myoblast proliferation and differentiation in vitro. However, the role of purinergic signaling during regeneration of injured skeletal muscle has not been investigated. To examine this process in a clinically relevant system, we used the mouse model of muscular dystrophy (mdx), in which muscle degeneration is rapidly followed by regeneration. The latter process, in vivo muscle regeneration, was the focus of this study, and to study the cellular mechanisms involved in it, a parallel study on normal rat skeletal myoblast cultures was conducted. Using immunohistochemistry, RT-PCR, and electrophysiology, we investigated the expression of the P2X1-7 receptor subtypes and the P2Y1,2,4,6 receptors. Experiments in vitro and in vivo demonstrated the sequential expression of the P2X5, P2Y1, and P2X2 receptors during the process of muscle regeneration. The P2X5 and P2Y1 receptors were expressed first on activated satellite cells, and the P2Y1 receptor was also expressed on infiltrating immune cells. Subsequent P2X2 receptor expression on newly formed myotubes showed significant colocalization with AChRs, suggesting a role in regulation of muscle innervation. Thus, this study provides the first evidence for a role for purinergic signaling in muscle regeneration and raises the possibility of new therapeutic strategies in the treatment of muscle disease.
PMID: 15231720 [PubMed - as supplied by publisher]
Purinoceptor expression in regenerating skeletal muscle in the mdx mouse model of muscular dystrophy and in satellite cell cultures.
Ryten M, Yang SY, Dunn PM, Goldspink G, Burnstock G.
ATP is an important extracellular signaling molecule mediating its effects by activation of P2X and P2Y receptors. P2 receptors are expressed during muscle development, and recent findings demonstrate that ATP can regulate myoblast proliferation and differentiation in vitro. However, the role of purinergic signaling during regeneration of injured skeletal muscle has not been investigated. To examine this process in a clinically relevant system, we used the mouse model of muscular dystrophy (mdx), in which muscle degeneration is rapidly followed by regeneration. The latter process, in vivo muscle regeneration, was the focus of this study, and to study the cellular mechanisms involved in it, a parallel study on normal rat skeletal myoblast cultures was conducted. Using immunohistochemistry, RT-PCR, and electrophysiology, we investigated the expression of the P2X1-7 receptor subtypes and the P2Y1,2,4,6 receptors. Experiments in vitro and in vivo demonstrated the sequential expression of the P2X5, P2Y1, and P2X2 receptors during the process of muscle regeneration. The P2X5 and P2Y1 receptors were expressed first on activated satellite cells, and the P2Y1 receptor was also expressed on infiltrating immune cells. Subsequent P2X2 receptor expression on newly formed myotubes showed significant colocalization with AChRs, suggesting a role in regulation of muscle innervation. Thus, this study provides the first evidence for a role for purinergic signaling in muscle regeneration and raises the possibility of new therapeutic strategies in the treatment of muscle disease.
PMID: 15231720 [PubMed - as supplied by publisher]
This one is also interesting as it shows that the satalite pool still stays elevated even with 60 days of detraining.
QUOTE
J Physiol. 2004 Jun 24 [Epub ahead of print] Related Articles, Links
The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles.
Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL.
Department of Physical Education and Health, Orebro University, Orebro, Sweden.
The aim of this study was to investigate the modulation of satellite cell content and myonuclear number following 30 and 90 days of resistance training and 3, 10, 30, 60 and 90 days of detraining. Muscle biopsies were obtained from the vastus lateralis of fifteen young men (mean age: 24 yrs; range: 20-32 yrs). Satellite cells and myonuclei were studied on muscle cross sections stained with a monoclonal antibody against CD56 and counterstained with Mayer's hematoxylin. Cell cycle markers CyclinD1 and p21 mRNA levels were determined by Northern blotting. Satellite cell content increased by 19% (P=0.02) at 30 days and by 31% (P=0.0003) at 90 days of training. Compared to pre-training values, the number of satellite cells remained significantly elevated at 3, 10 and 60 but not at 90 days of detraining. The two cell cycle markers CyclinD1 and p21 mRNA significantly increased at 30 days of training. At 90 days of training, p21 was still elevated whereas CyclinD1 returned to pre-training values. In the detraining period, p21 and CyclinD1 levels were similar to the pre-training values. There were no significant alterations in the number of myonuclei following the training and the detraining periods. The fibre area controlled by each myonucleus gradually increased throughout the training period and returned to pre-training values during detraining. In conclusion, these results demonstrate the high plasticity of satellite cells in response to training and detraining stimuli and clearly show that moderate changes in the size of skeletal muscle fibres can be achieved without the addition of new myonuclei.
PMID: 15218062 [PubMed - as supplied by publisher]
The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles.
Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL.
Department of Physical Education and Health, Orebro University, Orebro, Sweden.
The aim of this study was to investigate the modulation of satellite cell content and myonuclear number following 30 and 90 days of resistance training and 3, 10, 30, 60 and 90 days of detraining. Muscle biopsies were obtained from the vastus lateralis of fifteen young men (mean age: 24 yrs; range: 20-32 yrs). Satellite cells and myonuclei were studied on muscle cross sections stained with a monoclonal antibody against CD56 and counterstained with Mayer's hematoxylin. Cell cycle markers CyclinD1 and p21 mRNA levels were determined by Northern blotting. Satellite cell content increased by 19% (P=0.02) at 30 days and by 31% (P=0.0003) at 90 days of training. Compared to pre-training values, the number of satellite cells remained significantly elevated at 3, 10 and 60 but not at 90 days of detraining. The two cell cycle markers CyclinD1 and p21 mRNA significantly increased at 30 days of training. At 90 days of training, p21 was still elevated whereas CyclinD1 returned to pre-training values. In the detraining period, p21 and CyclinD1 levels were similar to the pre-training values. There were no significant alterations in the number of myonuclei following the training and the detraining periods. The fibre area controlled by each myonucleus gradually increased throughout the training period and returned to pre-training values during detraining. In conclusion, these results demonstrate the high plasticity of satellite cells in response to training and detraining stimuli and clearly show that moderate changes in the size of skeletal muscle fibres can be achieved without the addition of new myonuclei.
PMID: 15218062 [PubMed - as supplied by publisher]
This one is to cool not to post. Adipose stromal cells turn in to muscle?
QUOTE
Cell Transplant. 2004;13(2):103-11. Related Articles, Links
Transplantation of adipose tissue-derived stromal cells increases mass and functional capacity of damaged skeletal muscle.
Bacou F, el Andalousi RB, Daussin PA, Micallef JP, Levin JM, Chammas M, Casteilla L, Reyne Y, Nougues J.
UMR 866 Differenciation cellulaire et Croissance, INRA, Montpellier Cedex 1, France. francis.bacou@ensam.inra.fr
The regenerating skeletal muscle environment is capable of inducing uncommitted progenitors to terminally differentiate. The aim of this work was to determine whether adipose tissue-derived stromal cells were able to participate in muscle regeneration and to characterize the effect on muscle mass and functional capacities after transplantation of these cells. Adipose tissue stromal cells labeled with Adv cyto LacZ from 3-day-old primary cultures (SVF1) were autotransplanted into damaged tibialis anterior muscles. Fifteen days later, beta-galactosidase staining of regenerated fibers was detected, showing participation of these cells in muscle regeneration. Two months after SVF1 cell transfer, muscles were heavier, showed a significantly larger fiber section area, and developed a significantly higher maximal force compared with damaged control muscles. These results are similar to those previously obtained after satellite cell transplantation. However, SVF1 transfer also generated a small amount of adipose tissue localized along the needle course. To minimize these adipose contaminants, we transferred cells from 7-day-old secondary cultures of the SVF1, containing only a small proportion of already engaged preadipocytes (SVF2). Under these conditions, no adipose tissue was observed in regenerated muscle but there was also no effect on muscle performances compared with damaged control muscles. This result provides further evidence for the existence of progenitor cells in the stromal fraction of freshly isolated adipose tissue cells, which, under our conditions, keep some of their pluripotent properties in primary cultures.
PMID: 15129756 [PubMed - in process]
Transplantation of adipose tissue-derived stromal cells increases mass and functional capacity of damaged skeletal muscle.
Bacou F, el Andalousi RB, Daussin PA, Micallef JP, Levin JM, Chammas M, Casteilla L, Reyne Y, Nougues J.
UMR 866 Differenciation cellulaire et Croissance, INRA, Montpellier Cedex 1, France. francis.bacou@ensam.inra.fr
The regenerating skeletal muscle environment is capable of inducing uncommitted progenitors to terminally differentiate. The aim of this work was to determine whether adipose tissue-derived stromal cells were able to participate in muscle regeneration and to characterize the effect on muscle mass and functional capacities after transplantation of these cells. Adipose tissue stromal cells labeled with Adv cyto LacZ from 3-day-old primary cultures (SVF1) were autotransplanted into damaged tibialis anterior muscles. Fifteen days later, beta-galactosidase staining of regenerated fibers was detected, showing participation of these cells in muscle regeneration. Two months after SVF1 cell transfer, muscles were heavier, showed a significantly larger fiber section area, and developed a significantly higher maximal force compared with damaged control muscles. These results are similar to those previously obtained after satellite cell transplantation. However, SVF1 transfer also generated a small amount of adipose tissue localized along the needle course. To minimize these adipose contaminants, we transferred cells from 7-day-old secondary cultures of the SVF1, containing only a small proportion of already engaged preadipocytes (SVF2). Under these conditions, no adipose tissue was observed in regenerated muscle but there was also no effect on muscle performances compared with damaged control muscles. This result provides further evidence for the existence of progenitor cells in the stromal fraction of freshly isolated adipose tissue cells, which, under our conditions, keep some of their pluripotent properties in primary cultures.
PMID: 15129756 [PubMed - in process]
QUOTE
J Appl Physiol. 2004 Apr 30 [Epub ahead of print] Related Articles, Links
Satellite cell regulation of muscle mass is altered at old age.
Gallegly JC, Turesky NA, Strotman BA, Gurley CM, Peterson CA, Dupont-Versteegden EE.
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Muscle mass is decreased with advancing age likely due to altered regulation of muscle fiber size. This study was designed to investigate cellular mechanisms contributing to this process. Analysis of male F344/BN rats at 6, 20 and 32 months of age demonstrated that even though significant atrophy had occurred in soleus muscle by old age, myofiber nuclear number did not change, resulting in a decreased myonuclear domain. Also, the number of centrally located nuclei was significantly elevated in soleus muscle of 32 month-old rats, correlating with an increase in gene expression of MyoD and myogenin. Whereas total 5'-Bromo-2' deoxyuridine (BrdU) positive nuclei were decreased at older ages, BrdU positive myofiber nuclei were increased. These results suggest that with age, loss of muscle mass is accompanied by increased myofiber nuclear density that involves fusion of proliferative satellite cells, resembling ongoing regeneration. Interestingly, centrally located myofiber nuclei were not BrdU labeled. Rats were subjected to hind limb suspension (HS) for 7 or 14 days and intermittent reloading during HS for one hour each day (IR) to investigate how aging affects the response of soleus muscle to disuse and an atrophy-reducing intervention. After 14 days of HS soleus muscle size was decreased to a similar extent at all three ages. However, myofiber nuclear number and the total number of BrdU positive nuclei decreased with HS only in the young rats. IR was associated with an attenuation of atrophy in soleus muscles of 6 and 20, but not 32 month-old rats. Further, IR was associated with an increase in BrdU positive myofiber nuclei only in young rats. These data indicate that altered satellite cell function with age contributes to the impaired response of soleus muscle to an intervention that attenuates muscle atrophy in young animals during imposed disuse.
PMID: 15121742 [PubMed - as supplied by publisher]
Satellite cell regulation of muscle mass is altered at old age.
Gallegly JC, Turesky NA, Strotman BA, Gurley CM, Peterson CA, Dupont-Versteegden EE.
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Muscle mass is decreased with advancing age likely due to altered regulation of muscle fiber size. This study was designed to investigate cellular mechanisms contributing to this process. Analysis of male F344/BN rats at 6, 20 and 32 months of age demonstrated that even though significant atrophy had occurred in soleus muscle by old age, myofiber nuclear number did not change, resulting in a decreased myonuclear domain. Also, the number of centrally located nuclei was significantly elevated in soleus muscle of 32 month-old rats, correlating with an increase in gene expression of MyoD and myogenin. Whereas total 5'-Bromo-2' deoxyuridine (BrdU) positive nuclei were decreased at older ages, BrdU positive myofiber nuclei were increased. These results suggest that with age, loss of muscle mass is accompanied by increased myofiber nuclear density that involves fusion of proliferative satellite cells, resembling ongoing regeneration. Interestingly, centrally located myofiber nuclei were not BrdU labeled. Rats were subjected to hind limb suspension (HS) for 7 or 14 days and intermittent reloading during HS for one hour each day (IR) to investigate how aging affects the response of soleus muscle to disuse and an atrophy-reducing intervention. After 14 days of HS soleus muscle size was decreased to a similar extent at all three ages. However, myofiber nuclear number and the total number of BrdU positive nuclei decreased with HS only in the young rats. IR was associated with an attenuation of atrophy in soleus muscles of 6 and 20, but not 32 month-old rats. Further, IR was associated with an increase in BrdU positive myofiber nuclei only in young rats. These data indicate that altered satellite cell function with age contributes to the impaired response of soleus muscle to an intervention that attenuates muscle atrophy in young animals during imposed disuse.
PMID: 15121742 [PubMed - as supplied by publisher]
I thought this one was quite interesting nandi in light of your hypothesis. From this study it looks like old muscle is under constant regeneration. Maybe its this constant regeneration that depletes the cell pool. I also thought it was very interesting thta older mice do not show a drop in nuclei. What do you think the ramifications of that are? This constant regeneration might have something to do with the fact that myogenin is also generally elevated in old muscle.
Its looking more and more like myonulei donation is more about ensuring anti-catabolism during disuse by being permisive in the fast to slow transition, than it is about hypertrophy. This makes a lot of sense about why type II fibers die off in the elderly. If there muscle is unable to perform fast-slow conversion during unloading because of this constant repair process (brought about by excessive myogenin maybe?) then those fast fibers would undergo apoptosis.
QUOTE
Also, what of leukemias, where the subject has all of that destroyed via TBI, then replaced from a donor. Would you expect a much more finite number in such subjects? Or does this only destroy hemopoietic stem cells and not mesenchymal stem cells??
unknown, but considering that this is exactly how many of the studies are conducted it is interesting to think about.
QUOTE
These results suggest that with age, loss of muscle mass is accompanied by increased myofiber nuclear density that involves fusion of proliferative satellite cells, resembling ongoing regeneration
I thought this was interesting in that it contradicts the dogma (dogmatic during most of life evidently) that muscle maintains a constant nucear/cytoplasmic ratio. The last abstract you posted Spook suggests that myofibrillar nuclear number is increasing at the expense of a dwindling pool of satellite cells. That seems to be the case. Also Spook, with respect to Par's question you quoted, radiation therapy targets rapidly dividing cells, not the majority of mesenchymal stem cells. Hematopoietic stem cells are among the most rapidly dividing in the body, thats why they are killed off leaving (most of) the rest of the body intact.
Muscle Nerve. 2004 Jan;29(1):120-7.
Satellite cells and myonuclei in young and elderly women and men.
Kadi F, Charifi N, Denis C, Lexell J.
Department of Physical Education and Health, Orebro University, 70182 Orebro, Sweden. fawzi.kadi@ioh.oru.se
The overall aim of this study was to assess the effects of aging on the satellite cell population. Muscle biopsies were taken from the tibialis anterior muscle of healthy, moderately active young (age range, 20-32 years; n = 31) and elderly (age range, 70-83 years; n = 27) women and men with comparable physical activity pattern. Satellite cells and myonuclei were visualized using a monoclonal antibody against neural cell adhesion molecule and counterstained with Mayer's hematoxylin. An average of 211 (range, 192-241) muscle fibers were examined for each individual. Compared with the young women and men, the elderly subjects had a significantly lower (P < 0.011) number of satellite cells per muscle fiber but a significantly higher (P < 0.004) number of myonuclei per muscle fiber. The number of satellite cells relative to the total number of nuclei [satellite cells/(myonuclei + satellite cells)] was significantly lower in the elderly than in the young women and men. These results imply that a reduction in the satellite cell population occurs as a result of increasing age in healthy men and women.
Other research supports this not too surprising phenomenon of satellite cell decline. For example:
http://www.ncbi.nlm.nih.gov/entrez/query.f...t_uids=14729869
QUOTE
Its looking more and more like myonulei donation is more about ensuring anti-catabolism during disuse by being permisive in the fast to slow transition, than it is about hypertrophy.
I disagree. Myonuclei donation, or satellite cell fusion, or whatever one wants to call it is central to both processes. My original suggestion was that training and/or aas induced hypertrophy accelerates this loss of satellite cells and their stem cell precursors, putting limitations on just how big a person can get. It may not be that there is one single limiting factor, but I believe the finite capacity for satellite cell regeneration is an important one.
Maybe someday if i have time (and Justin is interested), I'll write an article on Notch signaling. All this gets more interesting to me as I age.
Science. 2003 Nov 28;302(5650):1575-7.
Notch-mediated restoration of regenerative potential to aged muscle.
Conboy IM, Conboy MJ, Smythe GM, Rando TA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA.
A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
Science. 2003 Nov 28;302(5650):1575-7.
Notch-mediated restoration of regenerative potential to aged muscle.
Conboy IM, Conboy MJ, Smythe GM, Rando TA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA.
A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
One example of increased telomerase activity on "demand" ...
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Telomerase induction in astrocytes of Sprague-Dawley rat after ischemic brain injury.
Baek S, Bu Y, Kim H, Kim H.
Department of Herbal Pharmacology, Graduate School of East-West Medical Science, Kyung Hee University, Seoul 130-701, South Korea.
Telomerase, a reverse transcriptase, consists of an RNA template and protein polymerase. This ribonucleoprotein protects the linearized chromosomal end region and elongates the telomere during chromosomal replication. Telomerase is not expressed in adult somatic cells but it shows high activity in most cells during embryonic development. We report, by RT-PCR and immunohistochemical results, that the induction of telomerase protein catalytic subunit (TERT) in transient middle cerebral artery occlusion induced brain injury. TERT mRNA emerged 24 h after ischemia. We examined which brain cell expressed TERT in the penumbra region of injured brain. The expression of TERT began from 24 h and remained until 5 days after ischemia. We identified that TERT was co-localized with the astrocyte marker, GFAP, at 3 days after ischemia. This is strong evidence that TERT is induced in astrocytes when the brain is damaged by ischemia, and that this enzyme may play an important role in ischemic brain injury.
PMID: 15158005 [PubMed - indexed for MEDLINE]
--------------------------
Telomerase induction in astrocytes of Sprague-Dawley rat after ischemic brain injury.
Baek S, Bu Y, Kim H, Kim H.
Department of Herbal Pharmacology, Graduate School of East-West Medical Science, Kyung Hee University, Seoul 130-701, South Korea.
Telomerase, a reverse transcriptase, consists of an RNA template and protein polymerase. This ribonucleoprotein protects the linearized chromosomal end region and elongates the telomere during chromosomal replication. Telomerase is not expressed in adult somatic cells but it shows high activity in most cells during embryonic development. We report, by RT-PCR and immunohistochemical results, that the induction of telomerase protein catalytic subunit (TERT) in transient middle cerebral artery occlusion induced brain injury. TERT mRNA emerged 24 h after ischemia. We examined which brain cell expressed TERT in the penumbra region of injured brain. The expression of TERT began from 24 h and remained until 5 days after ischemia. We identified that TERT was co-localized with the astrocyte marker, GFAP, at 3 days after ischemia. This is strong evidence that TERT is induced in astrocytes when the brain is damaged by ischemia, and that this enzyme may play an important role in ischemic brain injury.
PMID: 15158005 [PubMed - indexed for MEDLINE]
I admit, nandi's cited references show decreasing satellite cell population with age. On the other hand, I think it makes difference to body builders whether that decline is associated with general aging process or associated with the upper limit on the number of cell divisions satellite cells can go through. In the former case, bb'ing may not accelerate satellite cell depletion, whereas in the latter case, bb'ing would.
Edited:
Edited:
QUOTE(nandi12 @ Jul 9 2004, 11:20 PM)
Also Spook, with respect to Par's question you quoted, radiation therapy targets rapidly dividing cells, not the majority of mesenchymal stem cells. Hematopoietic stem cells are among the most rapidly dividing in the body, thats why they are killed off leaving (most of) the rest of the body intact.
But you did not address the other question about the ergogenic possibilities of eating fetuses!!!
QUOTE
But you did not address the other question about the ergogenic possibilities of eating fetuses!!!
That one was lost on me. My wife limits what I'm allowed to watch on TV and at the movies. I think a better solution, and one right up your alley, would be a transdermal fetal concoction. That should bypass any digestive enzymes. Hell, I bet you could go dumpster diving outside Planned Parenthood and get your raw materials for free
QUOTE(Par Deus @ Jul 10 2004, 10:49 AM)
But you did not address the other question about the ergogenic possibilities of eating fetuses!!!
Soylent Greenogen?
Nandi - I would definitely like to see an article/explanation/analysis of Notch-1 Delta ligands.
Eureka:
"In-vitro Fertilization Clinic/Restaurant"
"In-vitro Fertilization Clinic/Restaurant"
I second the request for a Notch 1 Delta ligand peice.
OK, I'll try as hard as I can to keep the focus away from Drosophila development to topics related to some of the things that have come up in this thread.
just bumping this for more discussion.
More discussion? I think we've all agreed on the eating fetuses thing.
QUOTE(Gene @ Oct 3 2004, 07:00 PM)
More discussion? I think we've all agreed on the eating fetuses thing.
you mean inject right?
what about hormones? will GH help?
so... there is more to it than the number of sattelite cells available.
spook add a fourth rate limiting factor to your list
4) NOTCH SIGNALING IS IMPAIRED
spook add a fourth rate limiting factor to your list
4) NOTCH SIGNALING IS IMPAIRED
QUOTE
MUSCLE STEM CELL ACTIVATION IN AGING: NOTCH SIGNALING AND THE ENHANCEMENT OF MUSCLE
REGENERATIVE POTENTIAL
Thomas A. Rando, MD, PhD (P)
Department of Neurology and Neurological Sciences, Stanford University School of Medicine and the Palo Alto VA Medical Center, Palo Alto, California, USA
In the setting of aging muscle, the ability of resident progenitor cells to maintain, repair, or replace injured tissue is a critical compensatory mechanism to avoid muscle loss. It is known that in aged muscle, there is a loss of regenerative potential compared with normal, young muscle. The focus of our recent work has been to understand the regulation of that regenerative potential by studying both the muscle stem cells themselves as well as the environment in which they reside and function. Under normal conditions, the Notch signaling pathway plays an important role in different phases of the activation, proliferation, commitment, and differentiation of the primary muscle stem cell, the satellite cell, and its progeny. Inhibition of Notch signaling profoundly impairs muscle regenerative potential. Intriguingly, with age, there is a failure of activation of this pathway in satellite cells in response to injury, and this accounts for much of the impaired regenerative potential of aged muscle. Among the key aspects of impaired Notch signaling in aged tissue is the failure to upregulate the expression of the Notch ligand, Delta. When Delta is not induced, the Notch signaling pathway is not activated and satellite cells fail to generate sufficient progeny for effective muscle
repair. However, when Notch signaling is directly stimulated, bypassing the need for ligand-induced activation, aged satellite cells are as effective in mediating effective regeneration as are young satellite cells. Therefore, the older satellite cells retain the intrinsic regenerative potential, and it is really the environment
that limits effective regeneration Furthermore, when muscles of aged mice are exposed for 6-8 weeks to the systemic milieu of younger animals by parabiotic pairings, the regeneration of the aged muscle is indistinguishable from that in the younger partners. This enhanced regenerative potential is paralleled by an
upregulation of Delta in response to injury in the aged muscle. Clearly, factors in young serum are capable of modifying the aged progenitor cells or their niche such that, in response to injury, aged muscle displays a youthful phenotype both at a molecular level and at a histological level. These studies suggest that the agerelated impairment of muscle regeneration may not be due to an irreversible loss of progenitor cells, or an irreversible loss of their potential, but may in fact be amenable to systemic treatment to promote more effective tissue repair and maintenance.
REGENERATIVE POTENTIAL
Thomas A. Rando, MD, PhD (P)
Department of Neurology and Neurological Sciences, Stanford University School of Medicine and the Palo Alto VA Medical Center, Palo Alto, California, USA
In the setting of aging muscle, the ability of resident progenitor cells to maintain, repair, or replace injured tissue is a critical compensatory mechanism to avoid muscle loss. It is known that in aged muscle, there is a loss of regenerative potential compared with normal, young muscle. The focus of our recent work has been to understand the regulation of that regenerative potential by studying both the muscle stem cells themselves as well as the environment in which they reside and function. Under normal conditions, the Notch signaling pathway plays an important role in different phases of the activation, proliferation, commitment, and differentiation of the primary muscle stem cell, the satellite cell, and its progeny. Inhibition of Notch signaling profoundly impairs muscle regenerative potential. Intriguingly, with age, there is a failure of activation of this pathway in satellite cells in response to injury, and this accounts for much of the impaired regenerative potential of aged muscle. Among the key aspects of impaired Notch signaling in aged tissue is the failure to upregulate the expression of the Notch ligand, Delta. When Delta is not induced, the Notch signaling pathway is not activated and satellite cells fail to generate sufficient progeny for effective muscle
repair. However, when Notch signaling is directly stimulated, bypassing the need for ligand-induced activation, aged satellite cells are as effective in mediating effective regeneration as are young satellite cells. Therefore, the older satellite cells retain the intrinsic regenerative potential, and it is really the environment
that limits effective regeneration Furthermore, when muscles of aged mice are exposed for 6-8 weeks to the systemic milieu of younger animals by parabiotic pairings, the regeneration of the aged muscle is indistinguishable from that in the younger partners. This enhanced regenerative potential is paralleled by an
upregulation of Delta in response to injury in the aged muscle. Clearly, factors in young serum are capable of modifying the aged progenitor cells or their niche such that, in response to injury, aged muscle displays a youthful phenotype both at a molecular level and at a histological level. These studies suggest that the agerelated impairment of muscle regeneration may not be due to an irreversible loss of progenitor cells, or an irreversible loss of their potential, but may in fact be amenable to systemic treatment to promote more effective tissue repair and maintenance.
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