Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have found that dystrophin, the large protein absent from people with Duchenne muscular dystrophy (DMD), plays a direct role in properly aligning microtubules, cell components that provide structure and organization to essential cellular functions. Without dystrophin, microtubules are disorganized and essential proteins may be mislocalized, contributing to the cell destruction during contraction that characterize the disease. This new information, say researchers, could provide additional benchmarks in the development of gene and other molecular therapies to restore the function of dystrophin, and reverse the pathology of the disease. The work was reported in the August 3 issue of the Journal of Cell Biology.

Although scientists have known for some time that gene mutations and the absence of dystrophin cause DMD, the mechanisms of the disease's characteristic muscle wasting and inflammation—along with the fatty and fibrous tissue accumulation that results when muscle cells tear—have not been well understood. This new study, utilizing protein biology analysis and the fluorescent imaging techniques and expertise of the Light Imaging Section in the NIAMS Intramural Research Program, shows a direct connection between dystrophin and microtubules. Microtubules, which have been described as the "rails" upon which cellular components are transported, do not go to the right places in the muscle cell when dystrophin is absent.

The research team included NIAMS' Evelyn Ralston, Ph.D.; James Ervasti, Ph.D., professor of biochemistry, molecular biology and biophysics at the University of Minnesota, Minneapolis; and other colleagues from those institutions. The scientists' discoveries were multiple. They examined extracts of healthy skeletal muscle and found evidence of direct interaction between dystrophin and microtubules that involved a protein called tubulin, a constituent component of microtubules, suggesting that dystrophin might be involved in stabilizing microtubules. In addition, their images of muscle from healthy mice revealed well-organized microtubules partially aligned with "bands" of dystrophin, while images from mdx mice showed microtubule disarray. This study contributes to a better understanding of the various important roles that dystrophin plays in the muscle cells. The development of effective gene or molecular therapies to restore complete function of dystrophin and reverse the pathology of DMD will depend on a thorough understanding of the activities of this protein and its interactions with other proteins.

Duchenne muscular dystrophy, the most common of the muscular dystrophies, is diagnosed in childhood and causes progressive loss of skeletal muscle strength and heart problems. The usually fatal genetic disorder primarily affects boys, although girls and women who carry the defective gene may show some symptoms. About one-third of cases reflect new mutations; the rest run in families.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Reference: Prins, KW, Humston JL, Mehta A, Tate V, Ralston E, Ervasti JM. Dystrophin is a microtubule-associated protein. J Cell Biol. 2009 Aug 3;186(3):363-369.