title: Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass.
abstract: Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body and muscle weights 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, we 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. We verified that p-Stat3, C/EBPδ, and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBPδ to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: lipingz@bcm.edu.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Jenny
authors.initials: J
authors.lastname: Pan
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Dong
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Dong
authors.forename: Giacomo
authors.initials: G
authors.lastname: Garibotto
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D055435:Myostatin; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D051743:CCAAT-Enhancer-Binding Protein-delta