Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

Anyone has any more details about this? I remember some reserach hinted that deflazacort+arginine would provide more benefit than deflaz alone. I do not feel that great about it after reading this:

 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone....

Background
Duchenne muscular dystrophy (DMD) is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD.

Methodology
We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial effects of short-term treatments.

Conclusions/Significance
Our findings demonstrate that arginine metabolism by arginase promotes fibrosis of muscle in muscular dystrophy and contributes to kyphosis. Our findings also show that long-term, dietary supplementation with arginine exacerbates fibrosis of dystrophic heart and muscles. Thus, commonly-practiced dietary supplementation with arginine by DMD patients has potential risk for increasing pathology when performed for long periods, despite reports of benefits acquired with short-term supplementation.

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Sure doesen't sound beneficial. This finding reinforces what our Neuro, K.Flanigan, said about using suppliments; we need to see proof they provide benefit prior to using them.
I will continue giving 25 grams of l-arginine per day. You will never have proof of long term benefit of anything until long after our sons are gone. Further, in Duchenne, there has been very little correlation between what works in a mouse and what works in a human. And there are constantly studies that contradict each other all over the place. Remember, it took a very long time until scientists and doctors even admitted the benefits of corticosteroids. I pay very little attention to mouse studies. Most of the scientists you meet would tell you that, if their son had Duchenne, they would be giving them these supplements. These science projects tell you very little. And no one is doing serious arginine studies in humans. Long term studies will never happen, especially in supplements. You gotta go with what you feel comfortable with. Don't look to the doctors. If I did, my son would have stopped walking years ago. Instead, he is walking at 14 and a half.
The issue of whether or not to supplement is a very personal one indeed. The bottom line is that you have to make the best decision for your family with the information you have available at the time - and not beat yourself up later if you find the outcome to be less than ideal ......

So where do I stand on supplementation? there seems to be this fallacy that providing more of the nutrients that are beneficial to our boys is a good thing - however there is such a thing as too much (ask anyone with hemochromatosis whether you can have too much iron and see what they say). Giving more of something does not mean the physiological process it is commonly associated with will increase - quite often if the body is already functioning at max saturation adding more will do nothing for the physiological process you wish to increase - however it may cause havoc on other organ systems.

If the boys are getting plenty of fresh fruit and veg you are already giving them all the nutrients they need. (plus delivering them this way ensures they burn more calories during the digestion process - which is beneficial for so many reasons)

So when it comes to our boys if you really want to make sure they have access to plenty of arginine give them a handful of raisins, nuts or popcorn - they're all great sources of this non essential amino acid. :D
WOW - 14 and 1/2 years and still walking. What do you attribute it to - supplements or perhaps light on the spectrum for DMD? If you don't mind, would you share what mutation your son has and what supplements you give him. Thanks Char Burke

Jeff Sobel said:
I will continue giving 25 grams of l-arginine per day. You will never have proof of long term benefit of anything until long after our sons are gone. Further, in Duchenne, there has been very little correlation between what works in a mouse and what works in a human. And there are constantly studies that contradict each other all over the place. Remember, it took a very long time until scientists and doctors even admitted the benefits of corticosteroids. I pay very little attention to mouse studies. Most of the scientists you meet would tell you that, if their son had Duchenne, they would be giving them these supplements. These science projects tell you very little. And no one is doing serious arginine studies in humans. Long term studies will never happen, especially in supplements. You gotta go with what you feel comfortable with. Don't look to the doctors. If I did, my son would have stopped walking years ago. Instead, he is walking at 14 and a half.
David has deletion of exons 8 and 9. Muscle biopsy showed absolutely no dystrophin. Obviously, there is some variation even among kids with no dystrophin. We have been non-stop with our pt and steroid and supplements. From 4 to 8.5 years, we did 12 days on, 9 days off prednisone. At 8.5 we went to daily deflazacort, which we continue. At 9.5, we started 4 mg aceon as preemptive measure (echo is still normal). We have a supplement program that we have followed, with occasional tweaks, since the age of 3. I am particularly a fan of l-arginine (used to give juven but I don't believe glutamine is beneficial) and we have been giving 25 grams a day for over 5 years (31 capsules, 16 in am 15 in pm). Obviously, the deflazacort works. I believe in the l-arginine and some of the other supplements we give. I, too, agree that more is not necessarily better. That's why I have stuck with the same dose of some supplements for over 10 years. Also, we give 5 grams creatine, but we cycle. 15 days on, 15 days off. Hard to say what is working, but if it's not broke, I don't fix it. We almost never skip any supplement dose. Persistence is key. I don't know how to private message on this board, and I don't want to put my email on board, but if there is private way to talk, I could get you a copy of my list.

Char Burke said:
WOW - 14 and 1/2 years and still walking. What do you attribute it to - supplements or perhaps light on the spectrum for DMD? If you don't mind, would you share what mutation your son has and what supplements you give him. Thanks Char Burke

Jeff Sobel said:
I will continue giving 25 grams of l-arginine per day. You will never have proof of long term benefit of anything until long after our sons are gone. Further, in Duchenne, there has been very little correlation between what works in a mouse and what works in a human. And there are constantly studies that contradict each other all over the place. Remember, it took a very long time until scientists and doctors even admitted the benefits of corticosteroids. I pay very little attention to mouse studies. Most of the scientists you meet would tell you that, if their son had Duchenne, they would be giving them these supplements. These science projects tell you very little. And no one is doing serious arginine studies in humans. Long term studies will never happen, especially in supplements. You gotta go with what you feel comfortable with. Don't look to the doctors. If I did, my son would have stopped walking years ago. Instead, he is walking at 14 and a half.
Hi; just to share some data that might or might not be useful. My son Hernán has a nonsense mutation (a stop codon that would make him a candidate for Ataluren if this drug ever takes off). His biobsy showed no traces of dystrophin. He stopped walking at age 16. We chose not to put him through tendon release surgery. He is close to 20 now. He has been on deflazacort since diagnosed at age 8. For a short time he also took creatine, but that was all. Because of the corticosteroids his growth was stalled, but fortunately his weight was never a problem. I suppose there is great variation among the different cases.
I forgot to add calcium and vitamin D of course, which my son has been taken since the beginning.

Bernardo A. Iriberri said:
Hi; just to share some data that might or might not be useful. My son Hernán has a nonsense mutation (a stop codon that would make him a candidate for Ataluren if this drug ever takes off). His biobsy showed no traces of dystrophin. He stopped walking at age 16. We chose not to put him through tendon release surgery. He is close to 20 now. He has been on deflazacort since diagnosed at age 8. For a short time he also took creatine, but that was all. Because of the corticosteroids his growth was stalled, but fortunately his weight was never a problem. I suppose there is great variation among the different cases.
Thanks for posting Bernardo. Based on a few cases of boys walking longer (13+ years), I am not yet convinced that the supplements make a significant difference. I've heard about several boys now not taking many supplements or even steroids very early on walking longer than some taking plenty of things. I still believe that genetic modifiers are more important than what we give to our sons. I do however believe that disease modifying treatments/drugs (when approved) could make a significant difference. Having said that, I am always trying to find some scientific evidence (even limited) that one supplement or another might help...my 2.5 yo son takes protandim, coq10 along with VitD3; it is just very difficult to know what to add to the mix, as well as the dose levels needed in order to make some difference.

Bernardo A. Iriberri said:
Hi; just to share some data that might or might not be useful. My son Hernán has a nonsense mutation (a stop codon that would make him a candidate for Ataluren if this drug ever takes off). His biobsy showed no traces of dystrophin. He stopped walking at age 16. We chose not to put him through tendon release surgery. He is close to 20 now. He has been on deflazacort since diagnosed at age 8. For a short time he also took creatine, but that was all. Because of the corticosteroids his growth was stalled, but fortunately his weight was never a problem. I suppose there is great variation among the different cases.
Thank you Ofelia. I do believe that the cumulative evidence for the beneficial effects of corticosteroids is quite strong, not only in terms of the boys' ability to walk but also with regards to their respiratory functions. Even though my son stopped growing because of deflazacort, I am still happy that he was able to walk for a longer time and also that his overall health has been quite good all this time.

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