Stat3 Activation Links a C/EBPδ to Myostatin Pathway to Stimulate Loss of Muscle Mass

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 delta (C/EBP delta) KO mice and C2C12 myotubes with knockdown of C/EBPd or myostatin, we determined that p-Stat3 initiates muscle wasting via C/EBP delta, stimulating myostatin, a negative muscle growth regulator. C/EBP delta KO also improved survival of CKD mice. We verified that p-Stat3, C/EBP delta, and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBP delta to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.