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Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid.

ABSTRACT: Investigation of activin-A (A) and myostatin (M) in human myometrium (HM) and leiomyoma (HL) will explain their involvement in human myometrial pathophysiology.We aimed to investigate A and M response and steroid regulation in HM. We also evaluated A and M expression and response in HL.Tissues were analyzed and cultured.Patients included fertile (in proliferative phase) and menopausal women undergoing hysterectomy.HM explant cultures were treated with A and M (for Smad-7 mRNA quantification) or estrogen and progesterone (for A and M mRNA quantification). A and M expression levels were also evaluated in menopausal (physiological absence of steroids) HM specimens. A and M and their receptors were evaluated in HL (n = 8, diameter 5-8 cm) compared with their matched HM. HL explants cultures were treated with A and M (for Smad7 mRNA quantification), and, to explain the absence of response, the levels of follistatin, follistatin-related gene (FLRG), and Cripto were evaluated.A and M increased Smad7 expression in HM explants. A and M mRNAs were both reduced after estradiol treatment, unchanged after progesterone treatment, but were higher in menopausal than fertile (in proliferative phase) specimens. A, M, and FLRG were expressed at higher levels in HL compared with adjacent HM, whereas the receptors, follistatin, and Smad7 mRNAs resulted unchanged. Cripto mRNA was expressed only in HL.A and M act on human HM and are regulated by steroids. In HL there is an increase of A, M, FLRG, and Cripto expression.

SUBMITTER: Ciarmela P

PROVIDER: S-EPMC3047220 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid.

Ciarmela Pasquapina P Bloise Enrrico E Gray Peter C PC Carrarelli Patrizia P Islam Md Soriful MS De Pascalis Flavio F Severi Filiberto Maria FM Vale Wylie W Castellucci Mario M Petraglia Felice F

The Journal of clinical endocrinology and metabolism 20101222 3

<h4>Context</h4>Investigation of activin-A (A) and myostatin (M) in human myometrium (HM) and leiomyoma (HL) will explain their involvement in human myometrial pathophysiology.<h4>Objective</h4>We aimed to investigate A and M response and steroid regulation in HM. We also evaluated A and M expression and response in HL.<h4>Design</h4>Tissues were analyzed and cultured.<h4>Patients</h4>Patients included fertile (in proliferative phase) and menopausal women undergoing hysterectomy.<h4>Intervention ...[more]

PMID: 21177794

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Project description:BackgroundOne of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit.MethodsTo investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone.ResultsWe show that muscle of Ercc1Δ/- progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm3 in treated progeroid mice vs. 0.14 mm3 in untreated mice, cortical bone volume; 0.30 mm3 in treated progeroid mice vs. 0.22 mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) and their severity reduced, overall sustaining health without affecting lifespan.ConclusionsThis study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.

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Dataset Information

Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid.

Publications

Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid.

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