Testosterone inhibits transforming growth factor-β signaling during myogenic differentiation and proliferation of mouse satellite cells: Potential role of follistatin in mediating testosterone action

Controlled ovarian hyperstimulation (COH) is the most common therapeutic protocol to obtain a considerable number of oocytes in IVF-ET cycles. To date, the risk factors affecting COH outcomes remain elusive. Growth differentiation factor 8 (GDF-8), a member of transforming growth factor β (TGF-β) superfamily, has been long discerned as a crucial growth factor in folliculogenesis, and the aberrant expression of GDF-8 is closely correlated with the reproductive diseases. However, less is known about the level of GDF-8 in IVF-ET patients with different ovarian response. In the present study, the potential risk factors correlated with ovarian response were explored using logistic regression analysis methods. Meanwhile, the expression changes of GDF-8 and its responsible cellular receptors in various ovarian response patients were determined. Our results showed that several factors were intensely related to poor ovarian response (POR), including aging, obesity, endometriosis, surgery history, and IVF treatment, while irregular menstrual cycles and PCOS contribute to hyperovarian response (HOR). Furthermore, POR patients exhibited a decrease in numbers of MII oocytes and available embryos, thereby manifesting a lower clinical pregnancy rate. The levels of GDF-8, ALK5, and ACVR2B in POR patients were higher compared with those in control groups, whereas the expression level of ACVR2A decreased in poor ovarian response patients. In addition, clinical correlation analysis results showed that the concentration of GDF-8 was negatively correlated with LH and estradiol concentration and antral follicle count. Collectively, our observations provide a novel insight of ovarian response–associated risk factors, highlighting the potential role of GDF-8 levels in ovarian response during COH process.

Download Full-text

The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

Molecular Biology of the Cell ◽

10.1091/mbc.9.6.1449 ◽

1998 ◽

Vol 9 (6) ◽

pp. 1449-1463 ◽

Cited By ~ 22

Author(s):

Gian Maria Fimia ◽

Vanesa Gottifredi ◽

Barbara Bellei ◽

Maria Rosaria Ricciardi ◽

Agostino Tafuri ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Growth Factor ◽

Cell Cycle Progression ◽

Transforming Growth Factor ◽

Myogenic Differentiation ◽

Transforming Growth Factor Β ◽

Large Tumor ◽

Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

Download Full-text

Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension

Circulation ◽

10.1161/circ.130.suppl_2.17285 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Lai-Ming Yung ◽

Samuel D Paskin-Flerlage ◽

Ivana Nikolic ◽

Scott Pearsall ◽

Ravindra Kumar ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Type I ◽

Rna Seq ◽

Differentiation Factor ◽

Group I ◽

Tgf Β1

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.

Download Full-text

Transforming growth factor–β in tissue fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20190103 ◽

2020 ◽

Vol 217 (3) ◽

Cited By ~ 6

Author(s):

Nikolaos G. Frangogiannis

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Cellular Targets ◽

Extracellular Matrix Molecules ◽

Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

Download Full-text