Molecular mechanisms of intensive care unit-acquired weakness

Bloch, Susannah; Polkey, Michael I.; Griffiths, Mark; Kemp, Paul R.

doi:10.1183/09031936.00090011

Cited by 73 publications

(79 citation statements)

References 164 publications

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“…However our data suggest that GDF-15 rather than myostatin is more likely to be a driver of acute muscle atrophy in this patient cohort. Circulating myostatin levels were, contrary to what was expected [7,8], suppressed in the acute phase and recovered in both wasted and non-wasting patients ( Figure 2). …”

Section: Discussionmentioning

confidence: 73%

“…Although it is a common problem, affecting at least 25% of patients admitted to critical care [2,3], our understanding of the underlying pathological mechanisms is limited. Sepsis, systemic inflammatory response syndrome, immobility and hyperglycaemia are all thought to be major aetiological risk factors for the development of ICUAP [1,[4][5][6][7]. However, elucidation of the molecular mechanisms involved in human cases is difficult and evidence has often been contradictory.…”

Section: Introductionmentioning

confidence: 99%

“…However, expression is increased in response to oxidative stress, hypoxia, inflammation and tissue damage in liver, brain, lung and vascular tissue [13,14]. These factors are all thought to be important in the development of ICUAP [7]. GDF-15 is increasingly implicated in several disease processes including cardiovascular disease [14], multiple cancers [15][16][17], pulmonary artery hypertension [18] and importantly cachexia [19].…”

Section: Introductionmentioning

confidence: 99%

“…Suppression of IGF-1 was observed in various animal models of sepsis and immobility [7] and in patients with severe ICUAP [21]. Although both increased myostatin and decreased IGF-1 have been implicated in the development of ICUAP, the relative pattern of change in the circulating levels of these mediators during the acute development of muscle wasting has not been established.…”

Section: Introductionmentioning

confidence: 99%

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Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Bloch

Lee

Wort

et al. 2013

Critical Care Medicine

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Objectives: Acute muscle wasting in the critically ill is common, and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass: insulin-like growth factor-1 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15), were measured over a week. It was hypothesised that patients who developed acute muscle wasting would show distinct patterns of change in these mediators.Design: A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting.Setting: Tertiary cardiothoracic referral centre: Royal Brompton Hospital, London, UK.Patients: 42 patients undergoing elective high-risk cardiothoracic surgery.Interventions: Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and main results: 23 of 42 patients (55%) developed quadriceps atrophy. There wasan acute decrease in IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the non-wasting group (p>0.05). IGF-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p<0.01) but did in the nonwasting group (p>0.05). Finally, we demonstrated that GDF-15 caused atrophy of myotubes in vitro. Conclusion:These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. GDF-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with Intensive care unit acquired paresis and other forms of acute muscle wasting.Abstract word count: 292

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Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Bloch

Lee

Wort

et al. 2013

Critical Care Medicine

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“…Factors of muscle dysfunction, such as ICUAW, include neuropathy and muscle protein degradation caused by inflammation, peripheral microcirculation disorder, increased insulin resistance, and abnormal energy metabolism due to mitochondrial dysfunction [134]. NMES improves these factors that promote muscle catabolism [135][136][137][138][139].…”

Section: Neuromuscular Electrical Stimulationmentioning

confidence: 99%

Skeletal Muscle Dysfunction in Critical Illness

Iida¹,

Sakuma²

2017

Physical Disabilities - Therapeutic Implications

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Despite improvements in critical illness survival rates with recent developments in medical care, many patients still have long-term physical disabilities following stays in the intensive care unit (ICU). Critical illness-induced muscle weakness, so-called ICU-acquired weakness (ICU-AW), is a common occurrence in approximately 50% of critically ill patients in the ICU requiring mechanical ventilation for >7 days. ICU-AW contributes to increases in duration of mechanical ventilation and lengths of ICU and hospital stays and may persist among survivors for several years after discharge. Risk factors for ICU-AW include systemic inflammatory responses, severe sepsis, muscle inactivity, hyperglycemia, and use of neuromuscular blockers. Thus, the development of muscle wasting is suggested to be associated with pathophysiological alterations leading to an imbalance between muscle proteolysis and proteosynthesis through several cellular signaling networks. This chapter presents a review of the literature regarding critical illness-induced muscle wasting and describes potential treatment of excessive muscle catabolism.

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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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Molecular mechanisms of intensive care unit-acquired weakness

Cited by 73 publications

References 164 publications

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Skeletal Muscle Dysfunction in Critical Illness

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

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