The Impact of Super-Relaxed Myosin on Diaphragm Dysfunction in Ventilated Patients

Background

Weak diaphragm contraction is a common problem in patients receiving mechanical ventilation in intensive care units (ICUs). This leads to difficulties in weaning patients off ventilators, increases mortality rates, and imposes a significant economic burden. Although animal studies have shown potential benefits of drug interventions, our understanding of the molecular mechanisms remains incomplete, and there are currently no effective treatments to improve diaphragm strength in these patients. Researchers have found that about 80% of ICU patients receiving mechanical ventilation experience diaphragm dysfunction during weaning. Traditionally, this was thought to be due to diaphragm atrophy, but over 50% of ICU patients do not exhibit diaphragm atrophy, suggesting other factors may be at play.

Source Introduction

This paper was jointly researched by multiple authors including Marloes van den berg, Zhonghua Shi, Wout J. Claassen, and others, with the main authors affiliated with institutions such as Amsterdam UMC, Bispebjerg Hospital, and the University of Copenhagen. The paper was published in the journal “Science Translational Medicine” on July 31, 2024.

Research Process

To understand how myosin in the super-relaxed (SRX) state affects respiratory muscle function, researchers compared diaphragm biopsy samples from 54 ICU patients and 27 non-ICU patients. The study integrated muscle fiber mechanics measurements, X-ray diffraction experiments, biochemical tests, and clinical data.

Research Subjects and Experimental Steps

1. Sample Collection: Diaphragm biopsy samples were collected from participating ICU patients and non-ICU patients.
2. Ultrastructure Analysis and X-ray Diffraction Experiments: Samples were tested for muscle fiber cross-sectional area (CSA), mechanical properties, and SRX state.
3. Biochemical Tests: Protein expression levels and phosphorylation states in the diaphragm were determined through Western blotting and mass spectrometry analysis.
4. Drug Intervention Experiments: Researchers attempted to restore diaphragm fiber contractility in vitro using compounds that activate troponin.

Main Findings

1. Reduced Muscle Fiber Contractility: Diaphragm muscle fibers from ICU patients showed significantly reduced maximum force (32μm) under gradually increasing calcium ion concentrations ([Ca2+]), indicating impaired contractility.
2. Increase in Super-Relaxed Myosin: X-ray diffraction experiments and biochemical tests revealed a significant increase in the SRX state of myosin in ICU patients’ diaphragms, hindering myosin-actin binding and resulting in weaker activation response to calcium ions compared to the control group.
3. Decreased Phosphorylation of Myosin Regulatory Light Chain (RLC): Linear mixed model analysis showed significantly reduced RLC phosphorylation in ICU patients’ diaphragms, which may be the cause of increased SRX state.
4. Effects of Drug Intervention: Two small molecule compounds, CK-3825076 and CK-3762601, which activate troponin, were shown to restore contractility in diaphragm fibers in vitro.

Discussion

The results indicate that the SRX state is an important mechanism in diaphragm dysfunction caused by mechanical ventilation. Comparisons with vastus lateralis muscle samples and experiments showed that the increase in SRX state is primarily a diaphragm-specific phenomenon, rather than a systemic muscle condition.

Significance and Application Value

By revealing the mechanism of SRX myosin in diaphragm dysfunction, the study provides important scientific basis for developing new treatments for diaphragm weakness in ICU patients. The success of drug intervention experiments also suggests that new drugs targeting sarcomere proteins can effectively increase the calcium sensitivity of diaphragm fibers, potentially helping patients wean off ventilators more smoothly.

Research Highlights

1. Mechanism Elucidation: First systematic explanation of the role of SRX state myosin in ICU mechanical ventilation-induced diaphragm dysfunction.
2. Comprehensive Experimental Design: Combined multiple experimental methods to analyze mechanical, biochemical, and molecular information holistically.
3. Strong Clinical Relevance: Research results have direct clinical application value and may optimize the weaning process for ICU patients.

Conclusion

This study reveals the molecular basis of increased super-relaxed myosin in the diaphragm under mechanical ventilation conditions and proposes a new strategy to restore diaphragm contractility using compounds that activate troponin. This provides important theoretical and experimental evidence for developing new treatment methods, potentially alleviating the suffering and economic burden of ICU patients.