Myostatin Is a Human Placental Product That Regulates Glucose Uptake

Mitchell, Murray D.; Osepchook, Claire C.; Leung, Kai-Cheung; McMahon, Christopher D.; Bass, J. J.

doi:10.1210/jc.2005-2361

Cited by 60 publications

(58 citation statements)

References 14 publications

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“…The effect of myostatin on placental glucose transport is mixed, with decreased glucose transport in a choriocarcinoma cell line (27) and increased transport in human placental explants (28). Myostatin also promotes extravillous trophoblast migration in vitro, which may alter placental development in vivo (29).…”

Section: Discussionmentioning

confidence: 99%

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

Oestreich

Kamp

McCray

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During fetal development, the uterine environment can have effects on offspring bone architecture and integrity that persist into adulthood; however, the biochemical and molecular mechanisms remain unknown. Myostatin is a negative regulator of muscle mass. Parental myostatin deficiency (Mstn tm1Sjl/+ ) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized that Mstn tm1Sjl/+ dams would also confer increased bone strength. In wild-type offspring, maternal myostatin deficiency altered fetal growth and calvarial collagen content of newborn mice and conferred a lasting impact on bone geometry and biomechanical integrity of offspring at 4 mo of age, the age of peak bone mass. Second, we sought to apply maternal myostatin deficiency to a mouse model with osteogenesis imperfecta (Col1a2 oim ), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of male Col1a2 oim/+ offspring from natural mating of Mstn tm1Sjl/+ dams to Col1a2 oim/+ sires had a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure compared with age, sex, and genotype-matched offspring from natural mating of Col1a2 oim/+ dams to Col1a2 oim/+ sires. Finally, increased bone biomechanical strength of Col1a2 oim/+ offspring that had been transferred into Mstn tm1Sjl/+ dams as blastocysts demonstrated that the effects of maternal myostatin deficiency were conferred by the postimplantation environment. Thus, targeting the gestational environment, and specifically prenatal myostatin pathways, provides a potential therapeutic window and an approach for treating osteogenesis imperfecta.osteogenesis imperfecta | developmental origins of health and disease | fetal programming | myostatin | bone health O steogenesis imperfecta (OI) is a genetically and clinically heterogeneous heritable connective tissue disorder characterized by anomalies in type I collagen-containing tissues, particularly bone. Clinical manifestations include osteopenia/osteoporosis, fractures, skeletal deformities, short stature, and skeletal muscle weakness. Current therapies entail use of antiresorptive drugs and surgical interventions but have limited success (1). New approaches that decrease fracture risk while minimizing long-term damage to bone integrity are greatly needed. Myostatin, or growth and differentiation factor 8 (GDF8), is a TGF-β family member and negative regulator of muscle growth and development. It is highly conserved across species, primarily expressed in muscle cells, and participates in paracrine and endocrine signaling (2). Recently, we and others have shown that inhibiting myostatin, either genetically or pharmacologically, increases muscle mass and improves bone microarchitecture (3) and mechanical strength (4) in the OI murine (Col1a2 oim ) model. In addition to regulating muscle growth postnatally, myostatin deficiency in the maternal environment increases muscle mass in ...

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Section: Discussionmentioning

confidence: 99%

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

Oestreich

Kamp

McCray

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, treatment of term placental explants with 1 g/mL of myostatin increased glucose uptake (16). Supporting myostatin's potential role in modulating glucose uptake, Chen et al (17) recently reported that myostatin treatment led to a dosedependent increase in glucose uptake in C2C12 myotubles and L6 myocytes.…”

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confidence: 93%

“…In human placentae, myostatin expression is negatively correlated with gestational age, with myostatin protein significantly higher in early and preterm placentae as compared with term placentae (16). Furthermore, treatment of term placental explants with 1 g/mL of myostatin increased glucose uptake (16).…”

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confidence: 98%

Myostatin Is Localized in Extravillous Trophoblast and Up-Regulates Migration

Peiris

Salomón

Payton

et al. 2014

The Journal of Clinical Endocrinology & Metabolism

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Context: Myostatin is a highly conserved secretory protein that negatively regulates muscle development by affecting both proliferation and differentiation of muscle cells. In human placentae the expression of myostatin is negatively correlated with gestational age, and in placental explants, myostatin acts to facilitate glucose uptake. Myostatin expression is known to be higher in the placentae of pregnancies complicated by preeclampsia. Proper placental development is crucial for a healthy and successful pregnancy. Alterations to the function of the placental cells after treatment with myostatin have not previously been published.Objective: This study investigated the localization of myostatin in extravillous trophoblast (EVT) of human placentae. Furthermore, the effect of myostatin treatment on the proliferative and migrative capabilities of these placental cells was investigated.Results: Myostatin is localized in EVT, as identified by the immunohistochemistry of third-trimester placentae and immunocytochemistry of first-trimester EVT isolations positively staining for myostatin and human leukocyte antigen-G. Treatment of an EVT cell line (HTR-8/SVneo) and primary isolated EVT with varied concentrations of myostatin resulted in a significant increase in the proliferation (HTR-8/SVneo; P Ͻ .0001) and migration (HTR-8/SVneo and primary isolated EVT; P Ͻ .05), with proliferation being dose dependent and migration being dose independent. Conclusions:Myostatin localization was positively identified in EVT. Myostatin positively affected proliferation (HTR-8/SVneo) and migration of EVT (HTR-8/SVneo and primary isolated EVT). For the first time, the effect of myostatin treatment on placental cells is described. The results provide a base from which further in vitro investigations on myostatin's ability to modulate placental cell function can be made. (J Clin Endocrinol Metab 99: E2288 -E2297, 2014)

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“…Wider functions of myostatin are supported by the discovery of myostatin expression in a number of different tissues, including brain (35), mammary (23), cardiac (39), adipose (28), endometrium (38), and human placenta (29). One particularly interesting finding is the changing myostatin expression throughout gestation in the human placenta.…”

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confidence: 99%

“…One particularly interesting finding is the changing myostatin expression throughout gestation in the human placenta. Mitchell et al (29) have shown that there is a negative correlation in human placenta between myostatin expression and gestational age, with a higher myostatin expression evident in preterm human placental tissues compared with term placental tissues. Additional in vitro studies also found that myostatin regulates glucose uptake in human placenta (3,29).…”

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confidence: 99%

Placental expression of myostatin and follistatin-like-3 protein in a model of developmental programming

Peiris

Ponnampalam

Osepchook

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Peiris HN, Ponnampalam AP, Osepchook CC, Mitchell MD, Green MP. Placental expression of myostatin and follistatin-like-3 protein in a model of developmental programming. Am J Physiol Endocrinol Metab 298: E854 -E861, 2010. First published January 26, 2010 doi:10.1152/ajpendo.00673.2009.-Maternal undernutrition during gestation is known to be detrimental to fetal development, leading to a propensity for metabolic disorders later in the adult lives of the offspring. Identifying possible mediators and physiological processes involved in modulating nutrient transport within the placenta is essential to prevent and/or develop treatments for the effects of aberrant nutrition, nutrient transfer, and detrimental changes to fetal development. A potential role for myostatin as a mediator of nutrient uptake and transport from the mother to the fetus was shown through the recent finding that myostatin acts within the human placenta to modulate glucose uptake and therefore homeostasis. The mRNA and protein expression of myostatin and its inhibitor, follistatin-like-3 (FSTL3), was studied in the placenta and skeletal muscle of a transgenerational Wistar rat model of gestational maternal undernutrition in which the F2 offspring postweaning consumed a high-fat (HF) diet. Alterations in placental characteristics and offspring phenotype, specifically glucose homeostasis, were evident in the transgenerationally undernourished (UNAD) group. Myostatin and FSTL3 protein expression were also higher (P Ͻ 0.05) in the placentae of the UNAD compared with the control group. At maturity, UNAD HF-fed animals had higher (P Ͻ 0.05) skeletal muscle expression of FSTL3 than control animals. In summary, maternal undernutrition during gestation results in the aberrant regulation of myostatin and FSTL3 in the placenta and skeletal muscle of subsequent generations. Myostatin, through the disruption of maternal nutrient supply to the fetus, may thus be a potential mediator of offspring phenotype.

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Myostatin Is a Human Placental Product That Regulates Glucose Uptake

Abstract: Myostatin is synthesized, released, and acts within the human placenta. It contributes to placental glucose homeostasis and may be a therapeutic target in diseases ranging from placental insufficiency to diabetes in pregnancy.

Cited by 60 publications

References 14 publications

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

Myostatin Is Localized in Extravillous Trophoblast and Up-Regulates Migration

Placental expression of myostatin and follistatin-like-3 protein in a model of developmental programming

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