Muscle wasting is a hallmark of a number of diseases, including cancer, bacterial sepsis, AIDS, diabetes, and end-stage heart, kidney and obstructive pulmonary disease. Muscle wasting can cause generalized weakness and debilitation and in its extreme, when respiratory muscles are involved, asphyxia and even death.
Dongsheng Cai, M.D., Ph.D., a postdoctoral Fellow at Joslin Diabetes Center and Steven Shoelson, M.D., Ph.D., Helen and Morton Adler Chair and Associate Research Director at Joslin Diabetes Center, and Professor of Medicine at Harvard Medical School in Boston, along with their colleagues at Joslin, Beth Israel Deaconess Medical Center, The Children's Hospital Boston, Spaulding Rehabilitation Hospital, and Regeneron Pharmaceuticals in Tarrytown, NY, used transgenic (genetically altered) mice to study the biochemical pathways underlying muscle wasting. Their studies zeroed in on a transcription factor called NF-kB, which is well known for its importance in immune cells but was previously not known to be a critical mediator of muscle wasting.
The investigators created two different strains of transgenic mice--MIKK mice, in which NF-kB was activated selectively in muscle tissue, and MISR mice, in which NF-kB activation was inhibited in muscle. The MIKK mice were viable and appeared normal at birth, but as they matured, their body weight was reduced due to decreases in skeletal muscle mass. Their muscle fibers were also smaller than those of their non-genetically altered littermates. On the other hand, the MISR mice were normal in terms of appearance, body weight, and individual muscle weight and histology (the appearance of cells under the microscope) throughout life.
High doses of drugs called salicylates have been shown to inhibit NF-kB activity, so the researchers studied the impact of these drugs on MIKK mice. In one protocol, they initiated treatment with salicylates after weaning in 4-week-old MIKK mice already affected by muscle wasting. The mice's body weights increased with salicylate treatment and, after six months of therapy, their body weight, muscle mass and muscle fiber size were nearly normal. In a prevention protocol, salicylate treatment was begun during gestation. In these latter mice, body weights and muscle mass were essentially normal throughout life.
The researchers also studied the effects of blocking NF-kB activation in mouse models of muscle wasting, including immobilization/denervation and cancer. The former is a model for the muscle wasting that occurs during disuse, such as when a limb is casted, or in spinal cord injuries. Inhibition of NF-kB in MISR mice was accompanied by a partial remission of denervation-induced muscle atrophy, including increased muscle mass and fiber size. Muscle wasting is a significant problem for patients with certain forms of cancer, where it seriously diminishes their quality of life. They found that the MISR mice with cancer were protected from loosing muscle mass, and the MISR mice had much better survival rates than did normal mice with cancer. Thus, selective NF-kB blockade in muscle decreased muscle wasting and prolonged survival in this mouse model of cancer.
"The discovery that NF-kB activation is sufficient to cause skeletal muscle atrophy in vivo and that blockage of the NF-kB pathway can ameliorate atrophy suggests a new set of drug targets for chemical intervention during cachexia, cancer, AIDS and other settings of atrophy," the authors conclude. "This is critically important because unfortunately there are currently no drugs approved for the treatment of skeletal muscle atrophy."
Other authors of the study included J. Daniel Frantz, Ph.D., Nicholas E. Tawa Jr., M.D., Ph.D., Peter A. Melendez, Ph.D., Byung-Chul Oh, Ph.D., Hart G.W. Lidov, M.D., Ph.D., Per-Olof Hasselgren, M.D., Ph.D., Walter R. Frontera, M.D., Ph.D., Jongsoon Lee, Ph.D., and David J. Glass, M.D. The study was funded by the National Institutes of Health and the American Diabetes Association.
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Journal
Cell