Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Journal of Cachexia, Sarcopenia and Muscle

Mihail Todiras¹  Steffen Weber‐Carstens²  Christian Butter³  Ilka Jorde⁴  Katrin Schmoeckel⁴  Barbara M. Bröker⁴  Stephan B. Felix⁵  Sibylle Schmidt⁶  Cristina Pablo‐Tortola⁶  Alexander Hahn⁶  Jens Fielitz⁶  Marcel Nowak⁶  Friedrich C. Luft⁶  Melanie Kny⁶  Ernst Jarosch⁷  Thomas Sommer⁷  Claus Scheidereit⁸  Michael Willenbrock⁸ 

[1] Cardiovascular hormones Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany;Department of Anesthesiology and Intensive Care Medicine, Campus Virchow‐Klinikum and Campus Charité Mitte Charité‐Universitätsmedizin Berlin Berlin Germany;Department of Cardiology Heart Center Brandenburg and Medical University Brandenburg (MHB) Bernau Germany;Department of Immunology, Institute of Immunology and Transfusion Medicine University Medicine Greifswald Germany;Department of Internal Medicine B, Cardiology University Medicine Greifswald Greifswald Germany;Experimental and Clinical Research Center, Charité‐Universitätsmedizin Berlin Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany;Intracellular Proteolysis Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany;Signal Transduction in Tumor Cells Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany;

关键词: Sepsis;    NF‐κB;    CLP;    Muscle atrophy;    ICUAW;   

DOI  :  10.1002/jcsm.12491

来源: DOAJ

【 摘 要 】

Abstract Background Critically ill patients frequently develop muscle atrophy and weakness in the intensive‐care‐unit setting [intensive care unit‐acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute‐phase response are major risk factors. We reported earlier that the acute‐phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation‐induced muscle atrophy. Methods We performed cell‐based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol‐Myers Squibb (BMS)‐345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation‐induced muscle atrophy and the effects of BMS‐345541 treatment. Results The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll‐like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor ‘kappa‐light‐chain‐enhancer' of activated B‐cells (NF‐κB) p65 via TLR2 and TLR4 leading to an increased binding of NF‐κB to NF‐κB response elements in the promoter region of its target genes resulting in an increased expression of NF‐κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF‐κB signalling by BMS‐345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS‐345541 diminished inflammation‐induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: −21.2% and BMS‐345541: −10.4%; P < 0.05), tibialis anterior (vehicle: −22.7% and BMS‐345541: −17.1%; P < 0.05) and soleus (vehicle: −21.1% and BMS‐345541: −11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross‐sectional area showed that BMS‐345541 reduced inflammation‐induced atrophy of slow/type I and fast/type II myofibers compared with vehicle‐treated septic mice. BMS‐345541 reversed the inflammation‐induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1. Conclusions SAA1 activates the TLR2/TLR4//NF‐κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF‐κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF‐κB p65 atrophy pathway could have utility in combatting ICUAW.

【 授权许可】

Unknown