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News

12-11-2014

CAN INGESTION OF DIETARY SUPPLEMENTS THAT CONTAIN ARGININE HAVE NEGATIVE CONSEQUENCES IN MUSCULAR DYSTROPHY?

Dietary supplementation with products that are enriched with the amino acid arginine is provided to some boys and men with DMD, although the consequences of supplemental arginine on the pathology of muscular dystrophy are not well-known. Scientists at the UCLA DMDRC have discovered that two populations of inflammatory macrophages called M1 macrophages and M2a macrophages can compete for the use of arginine in dystrophic muscle, and the results of that competition can affect the course of the pathology.

Using the mdx mouse model of DMD, UCLA DMDRC researchers have shown that M1 macrophages convert arginine to toxic free radicals that can kill muscle fibers. However, killing by muscle by M1 macrophages is kept in check by another population of macrophages, the M2a macrophages that are also present in dystrophic muscle. M2a macrophages compete with M1 macrophages for arginine, and convert the arginine to non-toxic molecules. However, increases in arginine concentration can increase its availability to M1 macrophages and increase their killing of muscle cells, even in the presence of M2a macrophages. These findings suggest that increased killing of muscle cells by inflammatory cells may be a short-term consequence of dietary supplementation with arginine in DMD.

Details of this study are available in the following publication.

Villalta, S.A., H.X. Nguyen, B. Deng, T. Gotoh and J.G. Tidball. 2009. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Human Molecular Genetics 18:482-496.



WHY DOES MUSCULAR DYSTROPHY CAUSE HEART DISEASE?

A large proportion of DMD patient deaths are attributable to cardiac dysfunction associated with ventricular fibrosis, arrhythmias and conduction abnormalities, although the relationships between the dystrophin mutation and the cardiac defects are unknown. Researchers at the UCLA Duchenne Muscular Dystrophy Research Center tested whether cardiac pathology in dystrophin-deficient mdx mice can be corrected by the elevated production of nitric oxide (NO) by the myocardium. Dystrophin-deficient mdx mice were produced in which there was myocardial expression of a neuronal nitric oxide synthase (nNOS) transgene. Expression of the transgene prevented the progressive ventricular fibrosis of mdx mice and greatly reduced myocarditis. Electrocardiographs (ECG) attained by radiotelemetry in mdx mice showed that the mice displayed cardiac abnormalities that are characteristic of DMD patients. All of the ECG abnormalities in mdx mice were improved or corrected by nNOS transgene expression. In addition, defects in mdx cardiac autonomic function, which were reflected by decreased heart rate variability, were significantly reduced by nNOS transgene expression. These findings indicate that increasing NO production by dystrophic hearts may have therapeutic value.

For details concerning this investigation, please see the publication:

Wehling-Henricks, M., M.C. Jordan, K.P. Roos, B. Deng and J. G. Tidball. 2005. Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium. Human Molecular Genetics 14: 1921-1933.





DOES OXIDATIVE STRESS CONTRIBUTE TO THE PATHOLOGY OF MUSCULAR DYSTROPHY?

Before the identification of the deficient proteins that underlie muscular dystrophies, such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge supports the likelihood that interactions between the primary genetic defect and disruptions in the normal production of free radicals contribute to the pathophysiology of muscular dystrophies. Current evidence indicates three general routes through which free radical production can be disrupted in dystrophin deficiency to contribute to the ensuing pathology. First, differences in free radical production can disrupt signaling processes in muscle and other tissues and thereby worsen pathology. Second, tissue responses to the presence of pathology can cause a shift in free radical production that can promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause further changes in the production and relative quantities of free radicals and thereby contribute to disease. Unfortunately, the complexity of the free radical-mediated processes that are perturbed in complex pathologies such as DMD make it difficult to develop therapeutic approaches founded on systemic administration of antioxidants. A summary of current knowledge concerning the relationship between free radicals and muscular dystrophy is provided in the following paper by DMDRC researchers:

Tidball, J.G. and M. Wehling-Henricks. 2007. The role of free radicals in the pathophysiology of muscular dystrophy. Journal of Applied Physiology 102:1677-1686.



RESEARCHERS AT OHIO STATE UNIVERSITY IN COLLABORATION WITH UCLA DMDRC RESEARCHERS IDENTIFY A NEW STRATEGY TO TREAT MUSCULAR DYSTROPHY.

Previous work by UCLA DMDRC researchers identified the immune system as an important factor that can increase the pathology of muscular dystrophy. But how can immune cell involvement in DMD be manipulated to reduce pathology? Collaborative research between scientists at Ohio State University and the UCLA DMDRC identified a specific mechanism through which the immune system affects the pathology of muscular dystrophy. The scientists found that molecular signaling through a system that involves the proteins IkappaB kinase and NF-kappaB is persistently elevated in immune cells and regenerative muscle fibers in muscular dystrophy. However, genetic modification of part of the NF-kappaB gene was sufficient to reduce pathology in mdx mice, a model of DMD. The researchers also showed that the specific pharmacological inhibition of the protein IKK resulted in improved pathology and muscle function in mdx mice. These results underscore the critical role of NF-kappaB in the progression of muscular dystrophy and suggest the IKK/NF-kappaB signaling pathway as a potential therapeutic target for DMD.

Details of this investigation are reported in:

Acharyya, S., S.A. Villalta, N. Bakkar, T. Bupha-Intr, P.M.L. Janssen, M. Carathers, M. Karin, Z. Li, A. Beg, S. Ghosh, Z. Sahenk, M. Weinstein, K.L. Gardner, J.A. Rafael-Fortney, J.G. Tidball, A.S. Baldwin and D.C. Guttridge. 2007. IKK/NF-kB signaling interplay in macrophages and myofibers promotes muscle wasting in Duchenne muscular dystrophy. Journal of Clinical Investigation 117:889-901.



UCLA DMDRC SCIENTISTS IDENTIFY A NEW MECHANISM THAT INCREASES PATHOLOGICAL FIBROSIS IN MUSCULAR DYSTROPHY.

Researchers at the UCLA DMDRC in collaboration with Dr. Jamie Lee at the Mayo Clinic have shown a surprising role for the immune cells called eosinophils in promoting the pathology of muscular dystrophy. Eosinophils are commonly involved in allergic reactions or in immune responses to parasites. However, DMDRC investigators find these cells increase muscle fibrosis in the mdx mouse model of muscular dystrophy. By treating mdx mice with antibodies that bound to a protein on the surface of eosinophils, the researchers were able to reduce injury to the cell membrane of muscle cells. In addition, mutating the gene for the eosinophil protein called major basic protein (MBP) reduced fibrosis of muscle and hearts, a major cause of mortality in DMD. Further experimentation showed that MBP can influence the nature of the immune response in muscular dystrophy, and contribute to a shift in inflammatory cells to a type that causes fibrosis of dystrophic muscles and hearts.

Further details of this investigation are reported in:

Wehling-Henricks, M., Sokolow, S., Lee, J.J., Myung, K.H., Villalta, S.A., and J.G. Tidball. 2008. Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Human Molecular Genetics 17:2280-2292.