Being diagnosed with certain illnesses, such as chronic kidney disease or diabetes, can lead to loss of muscle mass; it is an associated morbidity that at this time does not have a known cause or specific treatment. Researchers at Baylor College of Medicine have now identified in mouse models and patient muscle biopsies a new signaling pathway that could lead to a way of blocking the protein believed to be behind muscle wasting.
The findings, which appear in the journal Cell Metabolism, could be the first steps to developing a novel therapeutic approach to prevent this side effect.
"People who suffer from certain cancers and serious infections also find they have a wasting away of muscle mass leading to decreased quality of life and increased risk of death. Our findings could have implications in many diseases," said Dr. Liping Zhang, assistant professor of medicine at BCM. "For this study we focused on chronic kidney disease and diabetes."
Using muscle biopsies from patients diagnosed with chronic kidney disease, researchers found that transcription factor Stat3 was activated - a transcription factor works by regulating the actions of genes. The researchers believed that Stat3 could be the cause of muscle wasting, so they created mouse models that prevented the activation of Stat3 and found that loss of body and muscle weight was suppressed.
"We found that when Stat3 is activated it begins an interaction among proteins triggering the stimulation of myostatin, a protein that suppresses muscle growth," said Zhang.
Other mouse models were used to help identify those proteins that mediated the activation of myostatin, helping to identify the pathway leading from activation of Stat3 to stimulation of myostatin.
In muscle biopsies of patients with chronic kidney disease, there are similar changes in the levels of the same mediators found in the mouse models. This suggests the results could form the basis for developing therapeutic strategies in the future.
"We also tested a small molecule that inhibits the activation of Stat3 producing similar results," said Zhang. "While these results were observed in mouse models, we feel this could be the starting point in developing a drug to eventually treat or even prevent muscle wasting in some patients."
Others who took part in the study include Dr. Jenny Pan, assistant professor of medicine, Yanlan Dong, research assistant in medicine, Dr. David Tweardy, M.D. Anderson Foundation Chair, professor of medicine, chief of infectious diseases, and developer of the Stat3 inhibitor used in these studies, and Dr. William Mitch, Gordon A. Cain Chair in Nephrology, all of BCM; Dr. Yanjun Dong, formerly of BCM, currently with An Zhen Hospital - Capital Medical University in China; and Dr. Giacomo Garibotto, Genoa University, Italy.
Funding and support for the study includes support of Dr. and Mrs. Harold Selzman, grants from the Norman S. Coplon Extramural Research Foundation and the American Diabetic Association, NIH Grants R37-DK37175 and T32-DK62706, NIH grants R21-CA149783 and R41-CA153658 and grant RP100421from the Cancer Prevention and Research Institute of Texas, the Ministero dell’Università e della Ricerca Scientifica e Tecnologica and from Genoa University, Italy.