Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs

Bloch, Susannah; Lee, J Y; Syburra, Thomas; Rosendahl, Ulrich; Griffiths, Mark; Kemp, Paul R.; Polkey, Michael I.

doi:10.1136/thoraxjnl-2014-206225

Cited by 97 publications

(99 citation statements)

References 36 publications

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“…Interestingly, an increased expression of GDF-15 was associated with a reduced expression of some microRNAs involved in the regulation of muscle growth in patients hospitalized in intensive care (Bloch et al 2015). These findings suggest a direct role of GDF15 as a suppressor of muscle growth potentially involved in sarcopenia and, therefore, support GDF15 as a reliable biomarker.…”

Section: Accepted Manuscriptmentioning

confidence: 74%

Biomarkers in sarcopenia: A multifactorial approach

Curcio

Ferro

Basile

et al. 2016

Experimental Gerontology

166

147

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Section: Accepted Manuscriptmentioning

confidence: 74%

Biomarkers in sarcopenia: A multifactorial approach

Curcio

Ferro

Basile

et al. 2016

Experimental Gerontology

166

147

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“…It was previously shown that overexpression of Gdf15 in mice prevents dietinduced obesity and increases lifespan by activating adipose tissue as well as systemic energy metabolism [66,67]. Conversely, circulating levels of GDF15 are also highly elevated in patients with muscle atrophy [68] and in cancer patients with severe anorexia and weight loss [69] and chronic inflammation [70]. Hence, future studies are required to delineate the protective or detrimental role of GDF15 as mitochondrial stress-induced cytokine.…”

Section: Discussionmentioning

confidence: 99%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

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Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21 À/À ) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR mt ) and amino acid biosynthetic pathways did not require the presence of FGF21.Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

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“…Ligands from the transforming growth factor beta (TGF‐β) pathway are important regulators of muscle mass that are positively associated with muscle wasting in a variety of conditions. Both myostatin and growth differentiation factor 15 (GDF‐15) are elevated in a range of muscle wasting conditions and are able to promote atrophy . Myostatin promotes muscle wasting by activating the canonical TGF‐β signalling pathway via phosphorylation of SMAD proteins, leading to increased protein breakdown and autophagy .…”

Section: Introductionmentioning

confidence: 99%

“…The importance of the canonical TGF‐β signalling system in the control of muscle mass implies that miRNAs that alter the expression of components of the system will modify the sensitivity of individuals to atrophic signalling. For example, miR‐1 and miR‐181 suppress TGF‐β signalling either indirectly through the suppression of HDAC4 expression and the associated increase in follistatin expression in the case of miR‐1 or directly in the case of miR‐181 . As both miRNAs are suppressed by GDF‐15 in muscle, one effect of GDF‐15 will be to sensitize cells to TGF‐β and myostatin …”

Section: Introductionmentioning

confidence: 99%

miR‐422a suppresses SMAD4 protein expression and promotes resistance to muscle loss

Paúl

Lee

Donaldson

et al. 2017

J cachexia sarcopenia muscle

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BackgroundLoss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.MethodsThe effect of miR‐422a on SMAD4 expression and transforming growth factor (TGF)‐β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross‐sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).ResultsmiR‐422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR‐422a suppressed SMAD4 expression and inhibited TGF‐beta and bone morphogenetic protein‐dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU‐associated muscle weakness, quadriceps expression of miR‐422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre‐surgery levels of miR‐422a were inversely associated with the amount of muscle that would be lost in the first post‐operative week (r = −0.57, P < 0.001).ConclusionsThese data suggest that differences in miR‐422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF‐beta signalling in skeletal muscle.

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Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs

Cited by 97 publications

References 36 publications

Biomarkers in sarcopenia: A multifactorial approach

Biomarkers in sarcopenia: A multifactorial approach

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

miR‐422a suppresses SMAD4 protein expression and promotes resistance to muscle loss

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