PMID- 33284091 OWN - NLM STAT- MEDLINE DCOM- 20210208 LR - 20240214 IS - 1522-1555 (Electronic) IS - 0193-1849 (Print) IS - 0193-1849 (Linking) VI - 320 IP - 1 DP - 2021 Jan 1 TI - Myostatin deficiency not only prevents muscle wasting but also improves survival in septic mice. PG - E150-E159 LID - 10.1152/ajpendo.00161.2020 [doi] AB - Sepsis remains a leading cause of mortality in critically ill patients. Muscle wasting is a major complication of sepsis and negatively affects clinical outcomes. Despite intense investigation for many years, the molecular mechanisms underlying sepsis-related muscle wasting are not fully understood. In addition, a potential role of muscle wasting in disease development of sepsis has not been studied. Myostatin is a myokine that downregulates skeletal muscle mass. We studied the effects of myostatin deficiency on muscle wasting and other clinically relevant outcomes, including mortality and bacterial clearance, in mice. Myostatin deficiency prevented muscle atrophy along with inhibition of increases in muscle-specific RING finger protein 1 (MuRF-1) and atrogin-1 expression and phosphorylation of signal transducer and activator of transcription protein 3 (STAT3; major players of muscle wasting) in septic mice. Moreover, myostatin deficiency improved survival and bacterial clearance of septic mice. Sepsis-induced liver dysfunction, acute kidney injury, and neutrophil infiltration into the liver and kidney were consistently mitigated by myostatin deficiency, as indicated by plasma concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase activity in the organs. Myostatin deficiency also inhibited sepsis-induced increases in plasma high-mobility group protein B1 (HMGB1) and macrophage inhibitory cytokine (MIC)-1/growth differentiation factor (GDF)-15 concentrations. These results indicate that myostatin plays an important role not only in muscle wasting but also in other clinically relevant outcomes in septic mice. Furthermore, our data raise the possibility that muscle wasting may not be simply a complication, but myostatin-mediated muscle cachexia and related changes in muscle may actually drive the development of sepsis as well.NEW & NOTEWORTHY Muscle wasting is a major complication of sepsis, but its role in the disease development is not known. Myostatin deficiency improved bacterial clearance and survival and mitigated damage in the liver and kidney in septic mice, which paralleled prevention of muscle wasting. These results raise the possibility that muscle wasting may not simply be a complication of sepsis, but myostatin-mediated cachexic changes may have a role in impaired bacterial clearance and mortality in septic mice. FAU - Kobayashi, Masayuki AU - Kobayashi M AUID- ORCID: 0000-0003-2023-4720 AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts. FAU - Kasamatsu, Shingo AU - Kasamatsu S AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts. FAU - Shinozaki, Shohei AU - Shinozaki S AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts. FAU - Yasuhara, Shingo AU - Yasuhara S AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts. FAU - Kaneki, Masao AU - Kaneki M AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts. LA - eng GR - R01 GM115552/GM/NIGMS NIH HHS/United States GR - R01 GM117298/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201207 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Lipocalin-2) RN - 0 (Mstn protein, mouse) RN - 0 (Muscle Proteins) RN - 0 (Myostatin) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (Tripartite Motif Proteins) RN - 126469-30-5 (Lcn2 protein, mouse) RN - EC 2.3.2.27 (Trim63 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Acute Kidney Injury/genetics MH - Animals MH - Cachexia/genetics/prevention & control MH - Lipocalin-2/blood MH - Liver Diseases/etiology/genetics MH - Liver Function Tests MH - Male MH - Mice MH - Muscle Proteins/biosynthesis/genetics MH - Muscular Atrophy/*genetics/prevention & control MH - Myostatin/*deficiency/*genetics MH - Neutrophil Infiltration/genetics MH - Phosphorylation MH - STAT3 Transcription Factor/biosynthesis/genetics MH - Sepsis/*genetics/microbiology/mortality MH - Survival Analysis MH - Tripartite Motif Proteins/biosynthesis/genetics MH - Ubiquitin-Protein Ligases/biosynthesis/genetics PMC - PMC8194407 OTO - NOTNLM OT - bacterial clearance OT - mortality OT - muscle wasting OT - myostatin OT - sepsis COIS- No conflicts of interest, financial or otherwise, are declared by the authors. EDAT- 2020/12/08 06:00 MHDA- 2021/02/09 06:00 PMCR- 2022/01/01 CRDT- 2020/12/07 12:09 PHST- 2020/12/08 06:00 [pubmed] PHST- 2021/02/09 06:00 [medline] PHST- 2020/12/07 12:09 [entrez] PHST- 2022/01/01 00:00 [pmc-release] AID - E-00161-2020 [pii] AID - 10.1152/ajpendo.00161.2020 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2021 Jan 1;320(1):E150-E159. doi: 10.1152/ajpendo.00161.2020. Epub 2020 Dec 7.