Pork in a dish: So why arent DMD researchers not working on human stem cells?

http://www.foxnews.com/scitech/2010/01/15/scientists-turn-stem-cell...

 

 

To make pork in the lab, Post and colleagues isolate stem cells from pigs' muscle cells. They then put those cells into a nutrient-based soup that helps the cells replicate to the desired number.

So far the scientists have only succeeded in creating strips of meat about 1 centimeter (a half inch) long; to make a small pork chop, Post estimates it would take about 30 days of cell replication in the lab.

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There is small (to the best of my knowledge) cohort of scientists working on human duchenne muscle fibers - they have been successful at growing these mini muscle fibers in a dish. The dish is actually a platform set up to measure the force of contraction of any given or combination of given compounds. Initially the study was published in FASEB J in early June of 2009 (copy attached), co-authored by Dr. Brian Tseng and Dr. Herman Vandenburgh and performed on mdx mouse muscle fibers;


"There are many potential compounds of interest for effecting DMD intermediate therapies. With research that can test many in short time frames, acceleration of the search is possible.Potential compounds to attenuate loss of muscle strength in DMD include those that stimulate muscle protein synthesis (anabolic steroids and recombinant growth factors), inhibit muscle protein degradation (protease inhibitors), reduce inflammation (glucocorticoids), modulate cytokine levels (antitumor necrosis factor-α and nitric oxide stimulators), or stimulate muscle stem-cell proliferation/fusion into muscle fibers (antimyostatins).

The FASEB Journal, June 1, 2009, Automated drug screening with contractile muscle tissue engineered from dystrophic myoblastsHere are only a few compounds of interest, which appear to have the minimum research validation that warrants further testing:

L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo... The results of the current study suggest an additional potential pathway for this synergism with arginine or creatine, an increased energy supply."


Since June 1, 2009 - some of above testing has been replicated on human duchenne muscle fibers. And not surprisingly, the mdx mouse fibers acted differently than the human dmd muscle fibers when treated with compounds. Over 60 compounds - both supplements and FDA approved compounds (including a broad range of corticosteroids) have been put through screening for contractile force - the compounds that have shown improved force, on the human dmd cell line, will be tested in 2010 with an additional assay for injury and fatigue. The best candidates will HOPEFULLY be ushered off into human clinical trials - in 2010.

The goal of the project is to identify the best FDA approved and/or supplements to be given in combination with each other - a synergy of positive reaction - a cocktail - in less than 36 months - a treatment, a recommendation based on scientific evidence and human trials to keep the B/DMD population healthier until other curative strategies are developed...this generation of young men.

Also an important goal of the project is to discover what is NOT good for the duchenne muscle fiber, what given in combination with other compounds (such as corticosteroids) makes the human duchenne muscle fiber worse...are our well intentioned "cocktails" causing more harm than good - or is too much of one compound not a good thing.

These questions and many others, are currently on the agenda of a small group of parents and researchers, and they must be answered.

Your right - and my only question is, why aren't more scientist working on human duchenne muscle fibers...why so few lines available to researchers?

More to come from Compound Quest; short timeline, fiscally responsible - agenda open/transparent to all interested parties.
Attachments:
I wonder if this is b/c L-arginine is an NO Donor. Question is: how high a (L-arginine) dose should be use to obtain efficacy in DMD boys?

Nitric oxide reverses prednisolone-induced inactivation of muscle satellite cells

http://www3.interscience.wiley.com/journal/116843244/abstract?CRETR...

Jenna L. Betters, PhD, Jodi H.D. Long, PhD, Kathleen S. Howe, PhD, Randy W. Braith, PhD, Quinlyn A. Soltow, MS, Vitor A. Lira, MS, David S. Criswell, PhD *

Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

email: David S. Criswell (dcriswell@hhp.ufl.edu)

*Correspondence to David S. Criswell, Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

Funded by:
American Heart Association


Abstract

Long-term corticosteroid therapy causes myopathy and can inhibit regeneration of skeletal muscle. Therefore, we hypothesized that corticosteroid exposure reduces satellite cell activity in skeletal myofibers. Male Swiss-Webster mice were injected daily for 8 weeks with prednisolone (GC) or vehicle (control). Single myofibers were isolated from the gastrocnemius, centrifuged to mechanically activate satellite cells, and maintained in culture for 48 h. Both constitutive nitric oxide synthase (NOS) isoforms were reduced in muscle by GC treatment (nNOS: -30%, eNOS: -34%). Fewer myogenic (myoD+) cells emanated from GC myofibers compared to control (-61%, P < 0.05). Supplementation of culture media with the nitric oxide donor, diethylenetriamine NONOate (DETA-NO; 5-50 M), caused a dose-dependent increase in the number of myoD+ cells arising from both control and GC myofibers (P < 0.05), and 10 and 50 M DETA-NO eliminated the GC-induced deficit in myogenic cells (P > 0.05). Therefore, supplementation of GC myofibers with DETA-NO restores satellite cell activity to control levels. Nitric oxide production could be an important therapeutic target for the prevention of corticosteroid myopathy. Muscle Nerve, 2007


Christine said:
L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo...
A human clinical trial is warranted - A Double Blind, DOSE RANGING STUDY OF L-ARGININE IN STEROID TREATED DUCHENNE MUSCULAR DYSTROPHY. To provide information on the optimal dose or range of doses of the efficacy, safety and tolerability of L-arginine in patients with corticosteroid-treated Duchenne muscular dystrophy as measured by grip strength and other functional measures. Furthermore, to assess the pharmacokinetics of L-arginine at the administered doses.

The community at large should push for a study. It would be a cost - effective, a conservative, yet, effective human clinical trial with the above compounds – these compounds are already being used in this population (not making a new product, just fine tuning what we already have) - off label use. This type of study would have less obstacles of new novel compounds that have no history or safety data – making the timeline a whole lot shorter, availability to the compounds almost IMMEDIATE to the community – and the red tape of a large pharma/bio-tech company non existent.

Recent history of the past ten years or so shows us that there has been a population of young men using 14grams of Juven or L-Arginine per day with corticosteriods. I would suggest talking to the parents who have been following this regime for additional insight.


Ofelia Marin said:
I wonder if this is b/c L-arginine is an NO Donor. Question is: how high a (L-arginine) dose should be use to obtain efficacy in DMD boys?

Nitric oxide reverses prednisolone-induced inactivation of muscle satellite cells

http://www3.interscience.wiley.com/journal/116843244/abstract?CRETR...

Jenna L. Betters, PhD, Jodi H.D. Long, PhD, Kathleen S. Howe, PhD, Randy W. Braith, PhD, Quinlyn A. Soltow, MS, Vitor A. Lira, MS, David S. Criswell, PhD *

Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

email: David S. Criswell (dcriswell@hhp.ufl.edu)

*Correspondence to David S. Criswell, Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

Funded by:
American Heart Association


Abstract

Long-term corticosteroid therapy causes myopathy and can inhibit regeneration of skeletal muscle. Therefore, we hypothesized that corticosteroid exposure reduces satellite cell activity in skeletal myofibers. Male Swiss-Webster mice were injected daily for 8 weeks with prednisolone (GC) or vehicle (control). Single myofibers were isolated from the gastrocnemius, centrifuged to mechanically activate satellite cells, and maintained in culture for 48 h. Both constitutive nitric oxide synthase (NOS) isoforms were reduced in muscle by GC treatment (nNOS: -30%, eNOS: -34%). Fewer myogenic (myoD+) cells emanated from GC myofibers compared to control (-61%, P < 0.05). Supplementation of culture media with the nitric oxide donor, diethylenetriamine NONOate (DETA-NO; 5-50 M), caused a dose-dependent increase in the number of myoD+ cells arising from both control and GC myofibers (P < 0.05), and 10 and 50 M DETA-NO eliminated the GC-induced deficit in myogenic cells (P > 0.05). Therefore, supplementation of GC myofibers with DETA-NO restores satellite cell activity to control levels. Nitric oxide production could be an important therapeutic target for the prevention of corticosteroid myopathy. Muscle Nerve, 2007


Christine said:
L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo...
Christine-- you are so knowledgable about this. Just the person I was looking for, since I got the disturbing news yesterday that my son's cpk had jumped to almost 27,000 from a previous high of 20,300. He just turned 8, and just yesrday took his first juven pack. I was only going to give him 1 pack per day, since he only weighs 42 pounds. Should I give him 2? Hypothetically, should we expect the cpk to go down if the juven, when combined w/the deflaz, is helping to stabalize his muscles? I will ask Dr. Wong this in a couple weeks. In the meantime, my son has been doing well, and I am going to try and not worry about the cpk too much.

Christine said:
There is small (to the best of my knowledge) cohort of scientists working on human duchenne muscle fibers - they have been successful at growing these mini muscle fibers in a dish. The dish is actually a platform set up to measure the force of contraction of any given or combination of given compounds. Initially the study was published in FASEB J in early June of 2009 (copy attached), co-authored by Dr. Brian Tseng and Dr. Herman Vandenburgh and performed on mdx mouse muscle fibers;


"There are many potential compounds of interest for effecting DMD intermediate therapies. With research that can test many in short time frames, acceleration of the search is possible.Potential compounds to attenuate loss of muscle strength in DMD include those that stimulate muscle protein synthesis (anabolic steroids and recombinant growth factors), inhibit muscle protein degradation (protease inhibitors), reduce inflammation (glucocorticoids), modulate cytokine levels (antitumor necrosis factor-α and nitric oxide stimulators), or stimulate muscle stem-cell proliferation/fusion into muscle fibers (antimyostatins).

The FASEB Journal, June 1, 2009, Automated drug screening with contractile muscle tissue engineered from dystrophic myoblastsHere are only a few compounds of interest, which appear to have the minimum research validation that warrants further testing:

L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo... The results of the current study suggest an additional potential pathway for this synergism with arginine or creatine, an increased energy supply."


Since June 1, 2009 - some of above testing has been replicated on human duchenne muscle fibers. And not surprisingly, the mdx mouse fibers acted differently than the human dmd muscle fibers when treated with compounds. Over 60 compounds - both supplements and FDA approved compounds (including a broad range of corticosteroids) have been put through screening for contractile force - the compounds that have shown improved force, on the human dmd cell line, will be tested in 2010 with an additional assay for injury and fatigue. The best candidates will HOPEFULLY be ushered off into human clinical trials - in 2010.

The goal of the project is to identify the best FDA approved and/or supplements to be given in combination with each other - a synergy of positive reaction - a cocktail - in less than 36 months - a treatment, a recommendation based on scientific evidence and human trials to keep the B/DMD population healthier until other curative strategies are developed...this generation of young men.

Also an important goal of the project is to discover what is NOT good for the duchenne muscle fiber, what given in combination with other compounds (such as corticosteroids) makes the human duchenne muscle fiber worse...are our well intentioned "cocktails" causing more harm than good - or is too much of one compound not a good thing.

These questions and many others, are currently on the agenda of a small group of parents and researchers, and they must be answered.

Your right - and my only question is, why aren't more scientist working on human duchenne muscle fibers...why so few lines available to researchers?

More to come from Compound Quest; short timeline, fiscally responsible - agenda open/transparent to all interested parties.
I really do not think that you should expect the CK to decrease when using steroids + any supplements/vitamins. The fact that it is higher does not mean anything really. In fact, I think that the levels increase with increase in strength due to steroids (the boys are able to do more hence using their muscles more).

It is hoped to see a significant decrease in the CK level if/when a disease modifying treatment would be approved (i.e. exon skipping etc.). Other than that, the CK levels can vary a lot in DMD boys...if I remember correctly (?) they get lower when the boys are getting older and the muscles are replaced by adipose and connective tissue.

Regina said:
Christine-- you are so knowledgable about this. Just the person I was looking for, since I got the disturbing news yesterday that my son's cpk had jumped to almost 27,000 from a previous high of 20,300. He just turned 8, and just yesrday took his first juven pack. I was only going to give him 1 pack per day, since he only weighs 42 pounds. Should I give him 2? Hypothetically, should we expect the cpk to go down if the juven, when combined w/the deflaz, is helping to stabalize his muscles? I will ask Dr. Wong this in a couple weeks. In the meantime, my son has been doing well, and I am going to try and not worry about the cpk too much
I agree Christine. We really need a trial!

I think CINRG did something with steroids + glutamine and creatine...but not steroids+arginine unfortunately.

Something somewhat related is that combination of ibuprofen+NO donor used in Italy as a replacement to steroids...they did see good things using the NO donor in mice...hopefully we can learn something from the pilot study taking place now (in DMD, BMD patients)...

Christine said:
A human clinical trial is warranted - A Double Blind, DOSE RANGING STUDY OF L-ARGININE IN STEROID TREATED DUCHENNE MUSCULAR DYSTROPHY. To provide information on the optimal dose or range of doses of the efficacy, safety and tolerability of L-arginine in patients with corticosteroid-treated Duchenne muscular dystrophy as measured by grip strength and other functional measures. Furthermore, to assess the pharmacokinetics of L-arginine at the administered doses.

The community at large should push for a study. It would be a cost - effective, a conservative, yet, effective human clinical trial with the above compounds – these compounds are already being used in this population (not making a new product, just fine tuning what we already have) - off label use. This type of study would have less obstacles of new novel compounds that have no history or safety data – making the timeline a whole lot shorter, availability to the compounds almost IMMEDIATE to the community – and the red tape of a large pharma/bio-tech company non existent.

Recent history of the past ten years or so shows us that there has been a population of young men using 14grams of Juven or L-Arginine per day with corticosteriods. I would suggest talking to the parents who have been following this regime for additional insight
I think your question is WONDERFUL - and once again, is clear that a human clinical trial is needed to further assess the benefit, optimal dose and efficacy of L-Arginine on corticosteroid-treated DMD.

The research I am referring to in my response is an accelerated project targeted of readily available compounds; supplements and FDA approved agents, that would work in synergy to promote optimal muscle function without further injury to the muscle. This is not new compound work - simply using the compounds we have and finding which ones work best together - and identifying those that might be deleterious to the duchenne muscle fiber. As noted in the paper; FASEB J, an escalated dose of CoQ10 tested with the Myomics technology on the mdx mBams revealed a decrease in tetanic muscle force. How does this translate to the patient - could it mean a lesser dose is better than a higher dose? What it really means is we MUST determine correct dosing for this compound in this population via human clinical trials. An affordable, expedited screening process - like the Myomics technology - can help us identify the best combination/compound candidates, and those not worthy of further investigation - that have shown deleterious results (otherwise, our well intended efforts could be causing more harm than good). By using compounds that are already available, known to be safe - and screened by this new technology, expedition of candidates can move into human clinical trials - fast.

Considering a large portion of the Duchenne community is already using a corticosteroid, and there is some safety data on the use of L - Arginine (lots of published studies), furthered by the results published in FASEB J, it seems reasonable that this is a good place to start - as additional data is created with additional compounds and combinations - with good safety data - they too can be moved int trial to establish dosing and efficacy. Perhaps a treatment regime that provide support to all Duchenne individuals - regardless of mutation - in the not too distant future?

I feel strongly that a project of this scope, given short timelines with very realistic, tangible outcomes is worthy of the communities support.

Not sure that this will ever answer your question on your child's cpk level in response to one dose of Juven - but I think it can answer many other questions for mom's who are in the same dilemma.




Christine said:
A human clinical trial is warranted - A Double Blind, DOSE RANGING STUDY OF L-ARGININE IN STEROID TREATED DUCHENNE MUSCULAR DYSTROPHY. To provide information on the optimal dose or range of doses of the efficacy, safety and tolerability of L-arginine in patients with corticosteroid-treated Duchenne muscular dystrophy as measured by grip strength and other functional measures. Furthermore, to assess the pharmacokinetics of L-arginine at the administered doses.
The community at large should push for a study. It would be a cost - effective, a conservative, yet, effective human clinical trial with the above compounds – these compounds are already being used in this population (not making a new product, just fine tuning what we already have) - off label use. This type of study would have less obstacles of new novel compounds that have no history or safety data – making the timeline a whole lot shorter, availability to the compounds almost IMMEDIATE to the community – and the red tape of a large pharma/bio-tech company non existent. Recent history of the past ten years or so shows us that there has been a population of young men using 14grams of Juven or L-Arginine per day with corticosteriods. I would suggest talking to the parents who have been following this regime for additional insight.

Ofelia Marin said:
I wonder if this is b/c L-arginine is an NO Donor. Question is: how high a (L-arginine) dose should be use to obtain efficacy in DMD boys?

Nitric oxide reverses prednisolone-induced inactivation of muscle satellite cells http://www3.interscience.wiley.com/journal/116843244/abstract?CRETR... Jenna L. Betters, PhD, Jodi H.D. Long, PhD, Kathleen S. Howe, PhD, Randy W. Braith, PhD, Quinlyn A. Soltow, MS, Vitor A. Lira, MS, David S. Criswell, PhD *

Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

email: David S. Criswell (dcriswell@hhp.ufl.edu)

*Correspondence to David S. Criswell, Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

Funded by:
American Heart Association


Abstract

Long-term corticosteroid therapy causes myopathy and can inhibit regeneration of skeletal muscle. Therefore, we hypothesized that corticosteroid exposure reduces satellite cell activity in skeletal myofibers. Male Swiss-Webster mice were injected daily for 8 weeks with prednisolone (GC) or vehicle (control). Single myofibers were isolated from the gastrocnemius, centrifuged to mechanically activate satellite cells, and maintained in culture for 48 h. Both constitutive nitric oxide synthase (NOS) isoforms were reduced in muscle by GC treatment (nNOS: -30%, eNOS: -34%). Fewer myogenic (myoD+) cells emanated from GC myofibers compared to control (-61%, P < 0.05). Supplementation of culture media with the nitric oxide donor, diethylenetriamine NONOate (DETA-NO; 5-50 M), caused a dose-dependent increase in the number of myoD+ cells arising from both control and GC myofibers (P < 0.05), and 10 and 50 M DETA-NO eliminated the GC-induced deficit in myogenic cells (P > 0.05). Therefore, supplementation of GC myofibers with DETA-NO restores satellite cell activity to control levels. Nitric oxide production could be an important therapeutic target for the prevention of corticosteroid myopathy. Muscle Nerve, 2007


Christine said:
L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo...
Yes, I am aware - but would love to have the compounds tested quickly, without much added cost - in the myomics platform on the actual human DUCHENNE CELL LINE - lots of data could be obtained, time minimized and money saved for furthering curative therapies...if proven helpful -expedited to human trials and then to those who need it....

Christine said:
I think your question is WONDERFUL - and once again, is clear that a human clinical trial is needed to further assess the benefit, optimal dose and efficacy of L-Arginine on corticosteroid-treated DMD.

The research I am referring to in my response is an accelerated project targeted of readily available compounds; supplements and FDA approved agents, that would work in synergy to promote optimal muscle function without further injury to the muscle. This is not new compound work - simply using the compounds we have and finding which ones work best together - and identifying those that might be deleterious to the duchenne muscle fiber. As noted in the paper; FASEB J, an escalated dose of CoQ10 tested with the Myomics technology on the mdx mBams revealed a decrease in tetanic muscle force. How does this translate to the patient - could it mean a lesser dose is better than a higher dose? What it really means is we MUST determine correct dosing for this compound in this population via human clinical trials. An affordable, expedited screening process - like the Myomics technology - can help us identify the best combination/compound candidates, and those not worthy of further investigation - that have shown deleterious results (otherwise, our well intended efforts could be causing more harm than good). By using compounds that are already available, known to be safe - and screened by this new technology, expedition of candidates can move into human clinical trials - fast.

Considering a large portion of the Duchenne community is already using a corticosteroid, and there is some safety data on the use of L - Arginine (lots of published studies), furthered by the results published in FASEB J, it seems reasonable that this is a good place to start - as additional data is created with additional compounds and combinations - with good safety data - they too can be moved int trial to establish dosing and efficacy. Perhaps a treatment regime that provide support to all Duchenne individuals - regardless of mutation - in the not too distant future?

I feel strongly that a project of this scope, given short timelines with very realistic, tangible outcomes is worthy of the communities support.

Not sure that this will ever answer your question on your child's cpk level in response to one dose of Juven - but I think it can answer many other questions for mom's who are in the same dilemma.




Christine said:
A human clinical trial is warranted - A Double Blind, DOSE RANGING STUDY OF L-ARGININE IN STEROID TREATED DUCHENNE MUSCULAR DYSTROPHY. To provide information on the optimal dose or range of doses of the efficacy, safety and tolerability of L-arginine in patients with corticosteroid-treated Duchenne muscular dystrophy as measured by grip strength and other functional measures. Furthermore, to assess the pharmacokinetics of L-arginine at the administered doses.
The community at large should push for a study. It would be a cost - effective, a conservative, yet, effective human clinical trial with the above compounds – these compounds are already being used in this population (not making a new product, just fine tuning what we already have) - off label use. This type of study would have less obstacles of new novel compounds that have no history or safety data – making the timeline a whole lot shorter, availability to the compounds almost IMMEDIATE to the community – and the red tape of a large pharma/bio-tech company non existent. Recent history of the past ten years or so shows us that there has been a population of young men using 14grams of Juven or L-Arginine per day with corticosteriods. I would suggest talking to the parents who have been following this regime for additional insight.

Ofelia Marin said:
I wonder if this is b/c L-arginine is an NO Donor. Question is: how high a (L-arginine) dose should be use to obtain efficacy in DMD boys?

Nitric oxide reverses prednisolone-induced inactivation of muscle satellite cells http://www3.interscience.wiley.com/journal/116843244/abstract?CRETR... Jenna L. Betters, PhD, Jodi H.D. Long, PhD, Kathleen S. Howe, PhD, Randy W. Braith, PhD, Quinlyn A. Soltow, MS, Vitor A. Lira, MS, David S. Criswell, PhD *

Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

email: David S. Criswell (dcriswell@hhp.ufl.edu)

*Correspondence to David S. Criswell, Center for Exercise Science, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida 32611, USA

Funded by:
American Heart Association


Abstract

Long-term corticosteroid therapy causes myopathy and can inhibit regeneration of skeletal muscle. Therefore, we hypothesized that corticosteroid exposure reduces satellite cell activity in skeletal myofibers. Male Swiss-Webster mice were injected daily for 8 weeks with prednisolone (GC) or vehicle (control). Single myofibers were isolated from the gastrocnemius, centrifuged to mechanically activate satellite cells, and maintained in culture for 48 h. Both constitutive nitric oxide synthase (NOS) isoforms were reduced in muscle by GC treatment (nNOS: -30%, eNOS: -34%). Fewer myogenic (myoD+) cells emanated from GC myofibers compared to control (-61%, P < 0.05). Supplementation of culture media with the nitric oxide donor, diethylenetriamine NONOate (DETA-NO; 5-50 M), caused a dose-dependent increase in the number of myoD+ cells arising from both control and GC myofibers (P < 0.05), and 10 and 50 M DETA-NO eliminated the GC-induced deficit in myogenic cells (P > 0.05). Therefore, supplementation of GC myofibers with DETA-NO restores satellite cell activity to control levels. Nitric oxide production could be an important therapeutic target for the prevention of corticosteroid myopathy. Muscle Nerve, 2007


Christine said:
L Arginine and DeflazacortThe glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses... indicating a direct muscle mechanism by which they may be benefiting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions... of combinatorial therapies taken by some DMD patients.
...there was a strong synergism in mdx mBAM tetanic force with arginine plus deflazacort, as previously found in vivo...

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