Inhibiting a growth factor called myostatin in mice with chronic kidney disease halted the muscle wasting common in the disorder and even reduced inflammation, indicating a new strategy for treating muscle wasting, said researchers from Baylor College of Medicine in a report in The FASEB Journal.
"Preventing muscle wasting would be helpful because studies show that people who have lost muscle mass are more likely to suffer disability and death," said Dr. William Mitch, professor of medicine and chief of the section of nephrology at BCM. People with chronic kidney disease are often put on low protein diets to reduce the accumulation of waste products and hence, the stress on their failing organs.
"I was worried that we might be putting patients at risk for muscle wasting because we restricted the amount of protein in the diet. I decided to try to understand why kidney failure causes muscle wasting," he said.
He and his colleagues found that muscle wasting occurs when a system that targets proteins for degradation becomes activated. Too much acid, insulin resistance and other problems associated with kidney disease can turn on this ubiquitin-proteasome system.
Too much myostatin reduces muscle mass
Studies in mice with kidney disease showed that they had high levels of myostatin in their muscles. Myostatin is a growth factor that keeps the growth of muscle in balance. Too much myostatin and muscle mass is reduced.
Mitch and his colleagues decided to test a peptibody, a humanized antibody combined with peptides (specially linked amino acids) that halts the activity of myostatin. They used two groups of mice with kidney disease. One group received the peptibody; the other did not.
"The results were better than I anticipated," he said. "It certainly corrected the problem of muscle mass by increasing its synthesis and suppressing the breakdown of muscle proteins. It also reduced the amount of inflammation we see with chronic kidney disease. Inflammation begins the process by which patients lose muscle mass."
The researchers then took the work another step forward. They exposed muscle cells to tumor necrosis factor, a marker for inflammation. These exposed muscle cells had increased levels of myostatin, said Mitch. When they treated other muscle cells with myostatin, they found increased levels of interleukin-6, a protein that stimulates the breakdown of muscle protein.
Possibilities for range of diseases
The studies are still preliminary, Mitch cautions. However, if inhibiting myostatin can be accomplished in humans, it could expand beyond people with kidney disease.
"In theory, you could use this for anyone who has insulin resistance (a marker of diabetes or pre-diabetes) or too much acid in the system," he said. "That could mean people with diseases ranging from trauma to cancer to overwhelming systemic infections. For me, it was exciting because other than using low protein diets, it is one of the few things that actually works in chronic kidney disease."
Others who took part in this research include Drs. Liping Zhang, Vik Rajan, , Zhaoyong Hu and Jie Du and medical student Eugene Lin of BCM, Drs. H. Q. Han, Xiaolan Zhou, Yanping Song, and Hosung Min of Amgen in Thousand Oaks, California, and Dr. Xiaonan Wang of Emory University in Atlanta. Mitch is also the Gordon A. Cain Professor of Medicine.
Funding for this work came from Satellite Healthcare, the American Diabetes Association, the National Institutes of Health, Amgen, Inc., and a grant from Dr. and Mrs. Harold Selzman.