Mechano-signalling pathways in an experimental intensive critical illness myopathy model

被引:35
作者
Kalamgi, Rebeca Corpeno [1 ]
Salah, Heba [1 ]
Gastaldello, Stefano [1 ]
Martinez-Redondo, Vicente [1 ]
Ruas, Jorge L. [1 ]
Fury, Wen [2 ]
Bai, Yu [2 ]
Gromada, Jesper [2 ]
Sartori, Roberta [3 ,4 ]
Guttridge, Denis C. [5 ]
Sandri, Marco [3 ,4 ]
Larsson, Lars [1 ,6 ,7 ]
机构
[1] Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden
[2] Regeneron Pharmaceut, Tarrytown, NY 10591 USA
[3] Venetian Inst Mol Med, I-35131 Padua, Italy
[4] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy
[5] Ohio State Univ, Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[6] Karolinska Inst, Dept Clin Neurosci, Clin Neurophysiol, SE-17177 Stockholm, Sweden
[7] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2016年 / 594卷 / 15期
基金
瑞典研究理事会;
关键词
HISTONE DEACETYLASE INHIBITOR; ACUTE QUADRIPLEGIC MYOPATHY; MUSCLE PROTEIN-SYNTHESIS; CARE-UNIT MODEL; SKELETAL-MUSCLE; UBIQUITIN-PROTEASOME; SOLEUS MUSCLE; MITOCHONDRIAL FUSION; ATROPHY; RAT;
D O I
10.1113/JP271973
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The complete loss of mechanical stimuli of skeletal muscles, i.e. loss of external strain related to weight bearing and internal strain related to activation of contractile proteins, in mechanically ventilated, deeply sedated and/or pharmacologically paralysed intensive care unit (ICU) patients is an important factor triggering the critical illness myopathy (CIM). Using a unique experimental ICU rat model, mimicking basic ICU conditions, we have recently shown that mechanical silencing is a dominant factor triggering the preferential loss of myosin, muscle atrophy and decreased specific force in fast-and slow-twitch muscles and muscle fibres. The aim of this study is to gain improved understanding of the gene signature and molecular pathways regulating the process of mechanical activation of skeletal muscle that are affected by the ICU condition. We have focused on pathways controlling myofibrillar protein synthesis and degradation, mitochondrial homeostasis and apoptosis. We demonstrate that genes regulating mitochondrial dynamics, as well as mitophagy are induced by mechanical silencing and that these effects are counteracted by passive mechanical loading. In addition, the recently identified ubiquitin ligases Fbxo31 and SMART are induced by mechanical silencing, an induction that is reversed by passive mechanical loading. Thus, mechano-cell signalling events are identified which may play an important role for the improved clinical outcomes reported in response to the early mobilization and physical therapy in immobilized ICU patients.
引用
收藏
页码:4371 / 4388
页数:18
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