Activin-A Overexpression in the Murine Lung Causes Pathology That Simulates Acute Respiratory Distress Syndrome

Apostolou, Eirini; Stavropoulos, Athanasios; Sountoulidis, Alexandros; Xirakia, Charoula; Giaglis, Stavros; Protopapadakis, Evdokia; Ritis, Konstantinos; Mentzelopoulos, Spyros D.; Pasternack, Arja; Foster, Martyn; Ritvos, Olli; Tzelepis, George E.; Andreakos, Evangelos; Sideras, Paschalis

doi:10.1164/rccm.201105-0784oc

Cited by 55 publications

(96 citation statements)

References 39 publications

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“…The recombinant fusion protein was produced in house. It has been reported previously to normalize (LPS-or activin A overexpression-induced) lung pathology in a mouse model (5) and to increase muscle size in mdx mice (24). The ectodomain (ecd) of human sActRIIB was amplified via PCR with the following primers: 5=-GGACTAGTAACATGACGGCGCCCTGG-3= and 5=-CCAGATCTGCGGTGGGGGCTGTCGG-3= from a plasmid containing the human ActRIIB sequence (in pCR-Blunt II-TOPO AM2-G17 ActRIIB, IMAGE clone no.…”

Section: Methodsmentioning

confidence: 99%

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Hulmi

Oliveira

Silvennoinen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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136

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Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1–2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.

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Section: Methodsmentioning

confidence: 99%

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Hulmi

Oliveira

Silvennoinen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

136

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“…The recombinant fusion protein effectively blocking myostatin and activins (24) was produced and purified in house as described in detail earlier (4,22,24). In brief, the fusion protein contains the ectodomain (ecd) of human sActRIIB and a human IgG1 Fc domain.…”

Section: Animalsmentioning

confidence: 99%

Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice

Hulmi

Oliveira

Silvennoinen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Hulmi JJ, Oliveira BM, Silvennoinen M, Hoogaars WM, Pasternack A, Kainulainen H, Ritvos O. Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice. Am J Physiol Endocrinol Metab 305: E171-E182, 2013. First published May 14, 2013 doi:10.1152/ajpendo.00065.2013.-The importance of adequate levels of muscle size and function and physical activity is widely recognized. Myostatin/activin blocking increases skeletal muscle mass but may decrease muscle oxidative capacity and can thus be hypothesized to affect voluntary physical activity. Soluble activin receptor IIB (sActRIIB-Fc) was produced to block myostatin/activins. Modestly dystrophic mdx mice were injected with sActRIIB-Fc or PBS with or without voluntary wheel running exercise for 7 wk. Healthy mice served as controls. Running for 7 wk attenuated the sActRIIB-Fc-induced increase in body mass by decreasing fat mass. Running also enhanced/restored the markers of muscle oxidative capacity and autophagy in mdx mice to or above the levels of healthy mice. Voluntary running activity was decreased by sActRIIB-Fc during the first 3-4 wk correlating with increased body mass. Home cage physical activity of mice, quantified from the force plate signal, was decreased by sActRIIB-Fc the whole 7-wk treatment in sedentary mice. To understand what happens during the first weeks after sActRIIB-Fc administration, when mice are less active, healthy mice were injected with sActRIIB-Fc or PBS for 2 wk. During the sActRIIB-Fc-induced rapid 2-wk muscle growth period, oxidative capacity and autophagy were reduced, which may possibly explain the decreased running activity. These results show that increased muscle size and decreased markers of oxidative capacity and autophagy during the first weeks of myostatin/activin blocking are associated with decreased voluntary activity levels. Voluntary exercise in dystrophic mice enhances the markers of oxidative capacity and autophagy to or above the levels of healthy mice. myostatin; activin receptor IIB; exercise; skeletal muscle; hypertrophy ADEQUATE SIZE AND FUNCTION of skeletal muscle are of paramount importance for health (3,11,49,58,60). Duchenne muscular dystrophy (DMD) is a disease characterized by progressive wasting of skeletal muscle (28). Restoration of dystrophin expression in all muscles of the body is difficult, and the effectiveness of such treatment likely depends on the muscle quality of DMD patients. Therefore, approaches aimed at stimulation of muscle growth and function are being developed that may complement dystrophin restoration approaches.Type IIB activin receptors (ActRIIB) are expressed in skeletal muscle (21, 37) and mediate the signaling of myostatin and activins (37, 59). Myostatin and activin are efficiently blocked by systemic injection of a soluble ligand binding domain of ActRIIB fused to the Fc domain of IgG (sActRIIB-Fc) (38). sActRIIB-Fc rapidly increases muscle mass and function and alleviates the disease phenotype...

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“…Dysregulation of activin-A may contribute to the development of disease. Recently, increased expression of activin-A has been demonstrated in pulmonary hypertension [6], acute lung injury [7] and asthma [8]. Oxidative stress, Toll-like receptor ligands and inflammatory cytokines stimulate the expression and production of activin-A, which in turn regulates inflammatory cytokine release, explaining its role in inflammatory responses [7].…”

Section: @Erspublicationsmentioning

confidence: 99%

“…On one hand, activin-A promotes alveolar cell death and stimulates the production of pro-inflammatory cytokines, including IL-6. Furthermore, activin-A is increased following pulmonary lipopolysaccharide (LPS) exposure and follistatin reduces LPS-induced pulmonary inflammation in mice [7]. On the other hand, follistatin was shown to augment the production of pro-inflammatory cytokines in concerted action with TNF-a and IL-13 [8].…”

Section: @Erspublicationsmentioning

confidence: 99%

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Activin-A: active in inflammation in COPD

2014

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Activin-A Overexpression in the Murine Lung Causes Pathology That Simulates Acute Respiratory Distress Syndrome

Cited by 55 publications

References 39 publications

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice

Activin-A: active in inflammation in COPD

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