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Purpose <p>Critically ill patients requiring intensive care unit (ICU) admission suffer from muscle weakness that persists for years, compromising quality-of-life. The pathophysiology of this long-term weakness remains unclear. We hypothesized that former ICU-patients show a long-term abnormal RNA-expression profile, which may contribute to lower long-term strength and for which modifiable risk factors can be identified.</p> Methods <p>This pre-planned secondary analysis of the EPaNIC-trial compared muscle transcriptomes of 115 former ICU-patients 5&#xa0;years after critical illness and 30 matched controls with RNA-sequencing, followed by pathway&#xa0;over-representation and differential co-expression analyses of the differentially expressed RNAs. We used multivariable linear regression analyses to identify which of the abnormal RNA-expressions associated with the long-term muscle strength of the patients and to identify potential risk factors for the abnormal RNA-expressions.</p> Results <p>In former patients, 234 down-regulated and 116 up-regulated RNAs were identified after adjustment for age, sex, and BMI. Pathway over-representation and further molecular and histological analyses indicated impaired mitochondrial energy metabolism, disturbed lipid metabolism, and increased collagen formation/fibrosis in former patients. Abnormal muscle RNA-expression in former patients correlated with lower long-term muscle strength. Several treatments given in-ICU and at 5-year follow-up associated with abnormal RNA-expression, most notably in-ICU early parenteral nutrition (early&#xa0;PN) and glucocorticoid use.</p> Conclusion <p>Abnormal RNA-expression profiles 5&#xa0;years after critical illness suggest disrupted mitochondrial function, disturbed lipid metabolism, and fibrosis, associated with lower long-term muscle strength and partly attributable to possibly avoidable risk factors. These findings open perspectives for prevention and possibly treatment of long-term muscle weakness after critical illness.</p> Trial registration number and date <p>ClinicalTrials.gov-NCT00512122, July 31, 2007.</p>

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Altered muscle transcriptome as molecular basis of long-term muscle weakness in survivors from critical illness

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Ceren Uzun Ayar,
  • Fabian Güiza,
  • Inge Derese,
  • Lies Pauwels,
  • Sarah Vander Perre,
  • Isabel Pintelon,
  • Michaël Casaer,
  • Nathalie Van Aerde,
  • Greet Hermans,
  • Sarah Derde,
  • Lucas Kreiss,
  • Greet Van den Berghe,
  • Ilse Vanhorebeek

摘要

Purpose

Critically ill patients requiring intensive care unit (ICU) admission suffer from muscle weakness that persists for years, compromising quality-of-life. The pathophysiology of this long-term weakness remains unclear. We hypothesized that former ICU-patients show a long-term abnormal RNA-expression profile, which may contribute to lower long-term strength and for which modifiable risk factors can be identified.

Methods

This pre-planned secondary analysis of the EPaNIC-trial compared muscle transcriptomes of 115 former ICU-patients 5 years after critical illness and 30 matched controls with RNA-sequencing, followed by pathway over-representation and differential co-expression analyses of the differentially expressed RNAs. We used multivariable linear regression analyses to identify which of the abnormal RNA-expressions associated with the long-term muscle strength of the patients and to identify potential risk factors for the abnormal RNA-expressions.

Results

In former patients, 234 down-regulated and 116 up-regulated RNAs were identified after adjustment for age, sex, and BMI. Pathway over-representation and further molecular and histological analyses indicated impaired mitochondrial energy metabolism, disturbed lipid metabolism, and increased collagen formation/fibrosis in former patients. Abnormal muscle RNA-expression in former patients correlated with lower long-term muscle strength. Several treatments given in-ICU and at 5-year follow-up associated with abnormal RNA-expression, most notably in-ICU early parenteral nutrition (early PN) and glucocorticoid use.

Conclusion

Abnormal RNA-expression profiles 5 years after critical illness suggest disrupted mitochondrial function, disturbed lipid metabolism, and fibrosis, associated with lower long-term muscle strength and partly attributable to possibly avoidable risk factors. These findings open perspectives for prevention and possibly treatment of long-term muscle weakness after critical illness.

Trial registration number and date

ClinicalTrials.gov-NCT00512122, July 31, 2007.