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Author Spotlight: Unveiling Mitochondrial Function and Cellular Metabolic Adaptation in Metabolic Diseases
Published on: October 4, 2024
MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-acquired
Roser Farre Garros1, Richard Paul1,2, Martin Connolly1
11 Molecular Medicine Section and.
Rationale:
Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases, but the mechanisms by which this occurs are unclear.
Objectives:
To identify microRNAs (miRNAs) that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction.
Methods:
miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-β signaling in vitro and in vivo.
Measurements And Main Results:
miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (rRNA) expression, suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1, and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation, suggesting that miR-542-5p increased transforming growth factor-β signaling. In mice, miR-542 overexpression caused muscle wasting, and reduced mitochondrial function, 12S rRNA expression, and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased transforming growth factor-β signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery.
Conclusions:
Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Insights
Elevated microRNAs (miRNAs), specifically miR-542-3p/5p, contribute to muscle wasting in critical illness by impairing mitochondrial function and activating transforming growth factor-β signaling, leading to muscle atrophy.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Skeletal muscle wasting is a significant complication of critical illness and chronic diseases, with unclear underlying mechanisms.
- Understanding the molecular drivers of muscle loss is crucial for developing effective interventions.
Purpose of the Study:
- To identify specific microRNAs (miRNAs) elevated in patients experiencing muscle wasting.
- To elucidate the molecular pathways through which these miRNAs contribute to muscle dysfunction.
Main Methods:
- Quantification of miRNA-542-3p/5p in quadriceps muscle from patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW).
- In vitro and in vivo studies to assess the impact of miR-542-3p/5p on mitochondrial function and transforming growth factor-β signaling.
- Correlation analysis of miRNA levels with muscle loss in surgical patients.
Main Results:
- miR-542-3p/5p were significantly elevated in patients with ICUAW and chronic obstructive pulmonary disease.
- In vitro, miR-542-3p induced mitochondrial ribosomal stress, while miR-542-5p enhanced transforming growth factor-β signaling.
- In vivo, miR-542 overexpression in mice led to muscle wasting, reduced mitochondrial function, and altered SMAD signaling, mirroring findings in ICUAW patients.
- Preoperative miR-542-3p/5p levels correlated with postoperative muscle loss in aortic surgery patients.
Conclusions:
- Elevated miR-542-3p/5p are implicated in muscle atrophy in intensive care unit patients.
- These miRNAs promote muscle dysfunction by inducing mitochondrial dysfunction and activating SMAD2/3 phosphorylation.
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