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Published on: June 14, 2024
Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs
S A A Bloch1, J Y Lee1, T Syburra2
1Molecular Medicine, National Heart and Lung Institute, Imperial College, London, UK.
Rationale:
The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.
Objectives:
To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.
Methods:
In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.
Measurements And Main Results:
Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.
Conclusions:
GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.
Insights
Growth and differentiation factor-15 (GDF-15) and microRNAs are implicated in intensive care unit-acquired weakness (ICUAW) muscle atrophy. GDF-15 may increase TGF-β sensitivity by suppressing microRNAs, offering therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Muscle atrophy in intensive care unit-acquired weakness (ICUAW) lacks clear molecular understanding.
- Growth and differentiation factor-15 (GDF-15) is hypothesized to drive ICUAW atrophy via microRNA dysregulation.
Purpose of the Study:
- Investigate GDF-15 and microRNA expression in ICUAW patients.
- Elucidate the mechanisms of GDF-15-induced muscle atrophy in vitro and in vivo.
Main Methods:
- Observational study with muscle biopsies and blood sampling from 20 ICUAW patients and 7 controls.
- Analysis of mRNA and microRNA expression in muscle tissue.
- Quantification of plasma GDF-15 protein.
- In vitro experiments with GDF-15 treatment of C2C12 myotubes.
Main Results:
- Elevated plasma and muscle GDF-15 levels in ICUAW patients compared to controls.
- Significantly lower expression of muscle homeostasis-related microRNAs in ICUAW patients.
- GDF-15 treatment in vitro increased atrophy-related gene expression and decreased microRNA expression.
- Evidence suggests increased TGF-β signaling sensitivity in ICUAW muscle.
Conclusions:
- GDF-15 may promote ICUAW muscle atrophy by increasing TGF-β signaling sensitivity through microRNA suppression.
- GDF-15 and associated microRNAs represent potential therapeutic targets for ICUAW.
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