Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension

Moreira-Gonçalves, Daniel; Padrão, Ana Isabel; Ferreira, Rita; Justino, Joana; Nogueira-Ferreira, Rita; Neuparth, Maria João; Vitorino, Rui; Fonseca, Hélder; Silva, Ana Filipa; Duarte, José Alberto; Leite‐Moreira, Adelino F.; Henriques‐Coelho, Tiago

doi:10.1016/j.bbadis.2015.10.002

Cited by 22 publications

(28 citation statements)

References 49 publications

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“…The role of TGFβ proteins in muscle wasting in PAH has not been widely analysed, being limited to one study showing increased circulating myostatin in MCT-treated rats 29. We have identified, as is the case in ICUAW,12 COPD14 and cancer,30 that PAH-associated muscle loss may also be a GDF-15 driven phenomenon.…”

Section: Discussionmentioning

confidence: 91%

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

Garfield

Crosby

Shao

et al. 2018

Thorax

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IntroductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.MethodsGDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.ResultsCirculating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.ConclusionsCirculating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.Trial registration numberNCT01847716; Results.

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Section: Discussionmentioning

confidence: 91%

“…5(Z)-7-oxozeanol has been used to antagonise TAK1 in a number of animal models of disease including autoimmune diabetes35 and cerebral ischaemia 20. TAK1 inhibitors may be more successful than other more specific drugs aimed at antagonising muscle loss, as they have the potential to inhibit these synergistic muscle wasting pathways 29…”

Section: Discussionmentioning

confidence: 99%

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

Garfield

Crosby

Shao

et al. 2018

Thorax

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“…58 The skeletal muscle is particularly sensitive to insulin resistance and metabolic syndrome, and indeed, the skeletal muscle of PAH patients exhibits signs of such abnormalities as well as mitochondrial dysfunction ( Figure 2D). 59 Proteomic analysis of PAH skeletal muscles revealed decreased expression of PDH and increased expression of glycolytic enzymes (eg, lactate dehydrogenase), as well as abnormal mitochondrial morphology suggestive of a glycolytic metabolism shift. 59,60 This finding is significant because it suggests that the impaired mitochondrial and metabolic functions observed in the cardiopulmonary system are also present in extrapulmonary tissues.…”

Section: Altered Metabolism In Skeletal Musclementioning

confidence: 99%

“…Another study demonstrated that mitochondria isolated from the gastrocnemius muscle of MCT rats are characterized by ATP synthase activity, decreased expression of transcription factor A, mitochondrial (TFAM, a DNA-binding protein that activates transcription of mitochondrial DNA), and accumulation of oxidatively modified proteins, suggesting that mitochondria from these animals are unable to efficiently clear damaged or misfolded proteins, thus contributing to muscle atrophy in PAH. 59 Finally, while most studies focused on metabolic disorders in PAH, a recent study demonstrated that in a novel model of PH from heart failure with preserved ejection fraction (PH-HFpEF), chronic nitrite or metformin treatment reduce hyperglycemia and attenuate PH endpoints via a sirtuin 3 (SIRT3)-AMPK-GLUT4 dependent signaling pathway in the skeletal muscle, suggesting that glucose uptake and mitochondrial function in the skeletal muscle are linked to systemic glucose levels and pulmonary vascular function. 61…”

Section: Altered Metabolism In Skeletal Musclementioning

confidence: 99%

The Basic Science of Metabolism in Pulmonary Arterial Hypertension

Frump

Lahm

2018

Advances in Pulmonary Hypertension

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Pulmonary hypertension (PH) encompasses a group of progressive and incurable cardiopulmonary disorders characterized by pulmonary vascular remodeling and increased mean pulmonary artery pressure leading to right heart failure. Emerging data suggest a common etiology for the reported diverse molecular and physiological abnormalities observed in the pulmonary vasculature: the metabolic theory of PH. This theory proposes that aberrations in metabolism and mitochondrial function are a major underlying cause for the cellular and organ level PH phenotype. Additionally, the metabolic theory of PH provides a rationale for the observed metabolic defects in other organs and systems outside of the pulmonary vasculature, including the right ventricle (RV), immune system, and skeletal muscle. However, whether these metabolic changes are driving disease and the timing and extent of these aberrations are still unknown. This review highlights: 1) key examples of metabolic alterations in the pulmonary vasculature, RV, inflammatory cells, and skeletal muscle; 2) examples of promising therapeutic interventions directly modifying metabolism; and 3) key remaining questions about the role of metabolic remodeling in PH.

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“…Similarly, a switch to a less fatigue-resistant phenotype (lower proportions of slowtwitch fibres) and increased anaerobic metabolism have been demonstrated in the lower limb muscles of patients with PAH [82][83][84] . Furthermore, an anabolic/catabolic imbalance (increased proteolytic markers and reduced mitochondrial ATP production) has been recently demonstrated in the gastrocnemius and blood in an experimental model of PAH together with significant body and muscle weight loss 85 . In view of these findings, pulmonary rehabilitation and exercise training have recently gained a lot of attention in the scientific community to alleviate skeletal muscle dysfunction and exercise intolerance in patients with PAH 80,86 .…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Skeletal Muscle Dysfunction: From Chronic Respiratory Disease to Critically Ill Patients

Barreiro¹

2016

BRN

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Muscle dysfunction, defined as the loss of either strength or endurance properties of muscles, is a prominent comorbidity in chronic obstructive pulmonary disease (COPD) that leads to impairment of the patients' exercise capacity and quality of life. Chronic obstructive pulmonary disease skeletal muscle dysfunction may affect both respiratory and limb muscles. However, the latter are usually more severely affected. Importantly, survival and COPD mortality are negatively influenced by dysfunction of the lower limb muscles and poor muscle mass as measured by mid-thigh cross-sectional area. In the current review, we discuss the effects of skeletal muscle dysfunction and wasting on the outcome of COPD. Additionally, whether muscle dysfunction takes place in respiratory disorders other than COPD, such as cystic fibrosis, idiopathic pulmonary fibrosis, scoliosis, and pulmonary arterial hypertension along with critical illness, is also reviewed herein. Identification of skeletal muscle dysfunction should be included in the routine assessment of patients with chronic respiratory disorders and in critical care settings and should be considered as a relevant target for treatment. Corresponding author: Esther Barreiro, ebarreiro@imim.es

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Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension

Abstract: Henriques-Coelho, Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension, BBA -Molecular Basis of Disease (2015),

Cited by 22 publications

References 49 publications

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

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

The Basic Science of Metabolism in Pulmonary Arterial Hypertension

Skeletal Muscle Dysfunction: From Chronic Respiratory Disease to Critically Ill Patients

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