840 Myostatin Deficiency Inhibits Muscle Wasting and Improves Bacterial Clearance and Survival in Septic Mice

Abstract

Abstract Introduction Sepsis is a leading cause of the mortality of burn patients. Muscle wasting is a major complication of sepsis and burn injury and negatively affects clinical outcomes of patients with sepsis and burn injury. Myostatin (MSTN) is a myokine that causes muscle atrophy by activating the activin type 2 receptor (ActRII) pathway and myostatin deficiency increases skeletal muscle mass. However, a role of myostatin in critical illness (e.g., sepsis, burn injury)-induced muscle wasting has not yet been investigated. Moreover, a role of muscle wasting in immune suppression and mortality in sepsis is unknown. Methods Sepsis was induced by cecum ligation and puncture (CLP) in male MSTN-deficient mice at 8 weeks of age and age- and body weight (BW)-matched wild type (WT) mice. Survival was monitored for 14 days. Bacterial clearance was evaluated at 16 h after CLP by measuring bacterial load in the peritoneal cavity and circulation. The weight of gastrocnemius (GC), tibialis anterior (TA) and soleus (SOL) muscle and cross-sectional areas of GC were measured before and at 14 days after CLP. To evaluate neutrophil organ infiltration, myeloperoxidase (MPO) activity was measured in the liver and kidney at 16 h after CLP. To evaluate liver dysfunction, acute kidney injury and inflammatory response, plasma levels of AST, ALT, NGAL and high mobility group box 1 (HMGB1) were measured at 16 h after CLP. Protein expression of Murf-1 and Atrogin-1, key players in muscle wasting, and ActRIIB was evaluated in GC muscle by immunoblotting at 3 days and 16 h after CLP, respectively. Results MSTN deficiency increased skeletal muscle mass and inhibited sepsis-induced muscle wasting compared with BW-matched WT mice. Sepsis-induced increase in Murf-1, but not Atrogin-1, expression in muscle was attenuated by MSTN deficiency. CLP increased protein expression of ActRIIB in muscle. Moreover, MSTN deficiency reduced mortality of septic mice compared with age- and BW-matched WT mice. MSTN deficiency improved bacterial clearance and ameliorated increases in MPO activity in the liver and kidney and plasma concentrations of AST, ALT, NGAL and HMGB1 in septic mice. Conclusions Our data showed that MSTN deficiency inhibited muscle wasting and improved bacterial clearance and survival in septic mice. These data indicate that MSTN plays an important role in sepsis-induced muscle wasting. Moreover, our findings suggest that muscle wasting may not be just a complication of sepsis but a driver of sepsis development contributing to mortality of septic mice. This study also raises the possibility that muscle wasting and/or activation of the MSTN-ActRII pathway may exacerbate sepsis-induced immune dysfunction. Applicability of Research to Practice Our study identifies the MSTN-ActRII pathway as a novel, potential molecular target to ameliorate muscle wasting and improve survival of septic burned patients.