Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

Garfield, Benjamin; Crosby, Alexi; Shao, Dongmin; Yang, Peiran; Read, Cai; Sawiak, Stephen J.; Moore, Stephen D.; Parfitt, Lisa; Harries, Carl; Rice, M. J.; Paúl, Richard; Ormiston, Mark L.; Morrell, Nicholas W.; Polkey, Michael I.; Wort, Stephen J.; Kemp, Paul R.

doi:10.1136/thoraxjnl-2017-211440

Cited by 42 publications

(40 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent data from animal models showed that GDF15 is able to induce muscle fiber apoptosis (12,13), but also the ablation of GDF15 resulted in an amplified skeletal muscle post exercise stress response, with a bigger increase of markers of muscle stress (Atf3, Atf6, and Xbp1s) (14). In humans, circulating GDF15 levels are significantly higher in subjects with sarcopenia or muscle atrophy (15)(16)(17) with respect to healthy subjects of comparable age. Recent studies demonstrate that GDF15 levels are negatively correlated with skeletal muscle mass index, handgrip strength, muscle cross-sectional area and thickness (15,18).…”

Section: Introductionmentioning

confidence: 99%

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

et al. 2020

View full text Add to dashboard Cite

Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation.

show abstract

Section: Introductionmentioning

confidence: 99%

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In recent years, GDF-15, a protein of the TGF-β family, has been shown to be associated with muscle atrophy in some chronic diseases. It has also been proven to be an ideal biomarker for muscle and weight loss in patients with pulmonary hypertension [13]. GDF-15 is gradually receiving more attention in the field of critical care due to its possible involvement in the pathogenesis of ICU-AW [14].…”

Section: Discussionmentioning

confidence: 99%

Utility of Plasma GDF-15 for Diagnosis and Prognosis Assessment of ICU-Acquired Weakness in Mechanically Ventilated Patients: Prospective Observational Study

Xie

Liu

Zheng

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Objective. To identify the clinical correlations between plasma growth differentiation factor-15 (GDF-15), skeletal muscle function, and acute muscle wasting in ICU patients with mechanical ventilation. In addition, to investigate its diagnostic value for ICU-acquired weakness (ICU-AW) and its predictive value for 90-day survival in mechanically ventilated patients. Methods. 95 patients with acute respiratory failure, who required mechanical ventilation therapy, were randomly selected among hospitalized patients from June 2017 to January 2019. The plasma GDF-15 level was detected by ELISA, the rectus femoris cross-sectional area (RFcsa) was measured by ultrasound, and the patient’s muscle strength was assessed using the British Medical Research Council (MRC) muscle strength score on day 1, day 4, and day 7. Patients were divided into an ICU-AW group and a non-ICU-AW group according to their MRC-score on the 7th day. The differences in plasma GDF-15 level, MRC-score, and RFcsa between the two groups were compared on the 1st, 4th, and 7th day after being admitted to the ICU. Then, the correlations between plasma GDF-15 level, RFcsa loss, and MRC-score on day 7 were investigated. The receiver operating characteristic curve (ROC) was used to analyze the plasma GDF-15 level, RFcsa loss, and % decrease in RFcsa on the 7th day to the diagnosis of ICU-AW in mechanically ventilated patients. Moreover, the predictive value of GDF-15 on the 90-day survival status of patients was assessed using patient survival curves. Results. Based on whether the 7th day MRC-score was <48, 50 cases were included in the ICU-AW group and 45 cases in the non-ICU-AW group. The length of mechanical ventilation, ICU length of stay, and hospital length of stay were significantly longer in the ICU-AW group than in the non-ICU-AW group (all P<0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all P<0.001). The plasma GDF-15 level was significantly negatively correlated with the MRC-score (r = −0.60), while it was significantly positively correlated with the RFcsa loss (r = 0.18) and the % decrease in RFcsa (r = 0.16). Moreover, the RFcsa loss was significantly negatively correlated with the MRC-score (r = −0.27) (all P<0.001). The ROC curve analysis showed that plasma GDF-15 level, RFcsa loss, and % decrease in RFcsa on day 7 had predictive value for ICU-AW diagnosis in mechanically ventilated patients. More specifically, the area under the ROC curve (AUC) of GDF-15 was 0.904, the AUC of RFcsa loss was 0.873, and the AUC of % decrease in RFcsa was 0.886 (all P<0.001). The 90-day survival curve demonstrated that the survival rate of the high plasma GDF-15 level group was 54.00%, while that of the low plasma GDF-15 level group was 75.56%. The difference between the two groups was statistically significant (P<0.05). Conclusion. The plasma GDF-15 concentration level was significantly associated with skeletal muscle function and muscle wasting on day 7 in ICU patients with mechanical ventilation. Therefore, it can be concluded that the plasma GDF-15 level on the 7th day has a high diagnostic yield for ICU-acquired muscle weakness, and it can predict the 90-day survival status of ICU mechanically ventilated patients.

show abstract

“…Promotes proliferation and differentiation in fetal lung development (19) Maternal serum levels increase throughout during pregnancy (12) High serum levels in term neonates that decline postnatally (20) Upregulated in neonatal mice exposed to hyperoxia in vivo (21) Upregulated in pulmonary epithelial and endothelial cells exposed to hyperoxia (22) GDF15 loss leads to decreased cell viability and increased oxidative stress (23) Chronic Obstructive Pulmonary Disease (COPD) Higher serum levels are associated with increased morbidity and mortality (4,24) Mediates smoking-induced inflammation and cellular senescence (25)(26)(27) Promotes mucin production in ciliated epithelial cells (28) Exacerbates lung inflammation secondary to infection (29) Contributes to cachexia: GFRAL mediated signaling, induces lipolysis and promotes muscle wasting (30)(31)(32)(33) Pulmonary Hypertension (PH) Associated with prognosis and response to therapy (34)(35)(36) Levels increased in pediatric PH related to congenital heart disease (37) Associated with increase in right atrial and pulmonary capillary wedge pressure (34) Induces muscle atrophy that is reversed by TAK1 inhibitor (38) Promotes angiogenesis and hinders endothelial cell apoptosis (39,40) Lung Fibrosis Associated with disease severity (41) Associated with higher odds of interstitial lung abnormality (42) Activates fibroblasts and M2 macrophages (40) Prevents the activation of fibroblasts during lung remodeling (43) FIGURE 1 | Cellular senescence and lung disease across the lifespan: role of GDF15.…”

Section: Age/condition Role Of Gdf15 Referencesmentioning

confidence: 99%

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

et al. 2020

View full text Add to dashboard Cite

Growth Differentiation Factor 15 (GDF15) is a divergent member of transforming growth factor-beta (TGF-β) superfamily and is ubiquitously expressed, under normal physiological conditions. GDF15 expression increases during many pathological states and serves a marker of cellular stress. GDF15 has multiple and even paradoxical roles within a pathological condition, as its effects can be dose- and time-dependent and vary based on the targeted tissues and downstream pathways. GDF15 has emerged as one of the most recognized proteins as part of the senescence associated secretory phenotype. Cellular senescence plays a major role in many lung diseases across the life-span from bronchopulmonary dysplasia in the premature neonate to COPD and idiopathic pulmonary fibrosis in aged adults. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. Glial-cell-line-derived neurotrophic factor family receptor alpha-like (GFRAL) in the brain stem has been identified as the only validated GDF15 receptor and mediates GDF15-mediated anorexia and wasting. The mechanisms and pathways by which GDF15 exerts its pulmonary effects are being elucidated. GDF15 may also have an impact on the lung based on the changes in circulating levels or through the central action of GDF15 activating peripheral metabolic changes. This review focuses on the role of GDF15 in different lung diseases across the lifespan and its role in cellular senescence.

show abstract

Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

Cited by 42 publications

References 39 publications

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

Utility of Plasma GDF-15 for Diagnosis and Prognosis Assessment of ICU-Acquired Weakness in Mechanically Ventilated Patients: Prospective Observational Study

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

Contact Info

Product

Resources

About