Researchers at Houston’s Baylor College of Medicine (BCM) report that they’ve identified a new signaling pathway in mouse models and patient muscle biopsies that could point to a way toward developing a therapy that would block the protein believed to be behind muscle wasting associated with diseases like chronic kidney disease and diabetes.
The research findings were published this week in the journal Cell Metabolism under the title “Stat3 Activation Links a C/EBPδ to Myostatin Pathway to Stimulate Loss of Muscle Mass”. (Cell Metabolism, Volume 18, Issue 3, 368-379, 3 September 2013), and could represent first steps toward developing a novel therapeutic approach to preventing the muscle wasting side effect.
The report abstract notes that the mechanisms by which Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass are unclearly understood, but that in muscle biopsies from CKD patients, the BCM researchers found activated signal transducer and activator of transcription 3 (Stat3 or p-Stat3), a transcription factor protein that works by regulating the actions of genes and is encoded in humans by the STAT3 gene.
The scientists hypothesized that p-Stat3 initiates muscle wasting, and created mice with muscle-specific knockout (KO) that prevents activation of Stat3, observing that in these mice, body and muscle weight losses were suppressed in models with CKD or acute diabetes. A small-molecule that inhibits Stat3 activation produced similar responses, suggesting a potential for translation strategies. Using CCAAT/enhancer-binding protein δ (C/EBPδ) KO mice and C2C12 myotubes with knockdown of C/EBPδ or myostatin, they determined that p-Stat3 initiates muscle wasting via C/EBPδ, stimulating myostatin, a negative muscle growth regulator. C/EBPδ KO also improved survival of CKD mice. Using muscle biopsies from patients diagnosed with chronic kidney disease, the researchers verified that p-Stat3, C/EBPδ, and myostatin were increased in muscles of CKD patients, concluding that the pathway from p-Stat3 to C/EBPδ to myostatin and deducing that muscle wasting could identify therapeutic targets that prevent muscle wasting. To test the hypothesis, they created mouse models that prevented 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,” says ays Dr. Liping Zhang, assistant professor of medicine at BCM in a release, noting that: “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. For this study we focused on chronic kidney disease and diabetes.”
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.
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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, suggesting that 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,” says Dr. 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.”
Also participating in the study were 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.
The Baylor College of Medicine Nephrology Division conducts basic and clinical research on kidney function and diseases. Internationally renowned research efforts focus upon the cellular and molecular biology of renal injury and hypertension and the molecular biology of osmotically induced stress in renal tubular cells.
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