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

Abstract

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 ...

Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta

“…The +/G610C muscle response to genetic myostatin inhibition closely mirrored that of heterozygous +/oim mice with inherent myostatin deficiency ( +/oim +/mstn ) as previously reported. ( 5,34 ) However, in +/ oim mice, the response was more robust, with observed increases and restoration of the trabecular and bone biomechanical properties to Wt levels. ( 5 ) The divergent treatment outcomes echo several recent studies suggesting the influence of mutation and disease severity on treatment efficacy in OI.…”

“…Differences were considered significant at p ≤ 0.1. The congenital study was not powered to test differences as a consequence of dam genotype, (34 ) and no significant differences were observed in bone parameters based on maternal genotype. Therefore, offspring of the same genotype and sex were combined for analyses regardless of maternal genotype.…”

“…( 33 ) In 2016, Oestreich and colleagues also reported that congenital deficiency of myostatin improves femoral bone strength in adulthood in both wild‐type (Wt) and heterozygote osteogenesis imperfecta murine model ( +/oim ) offspring. ( 34 )…”

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

“…Heterozygote oim (+/oim) mice model mild human OI whereas homozygote oim (oim/oim) model a severe phenotype (Saban et al, 1996). In a recent study by Oestreich and colleagues, Wt and +/oim offspring born to myostatin deficient dams exhibit improved skeletal phenotypes in adulthood compared to those born to Wt and +/oim dams (Oestreich et al, 2016b). To investigate whether intrinsic biological processes pre-or post-implantation were driving the changes, +/oim embryos were transferred to +/mstn dams and +/oim dams (control) at d3.5 gestational age.…”

Myostatin promotes the epithelial‐to‐mesenchymal transition of the dermomyotome during somitogenesis

“…MSTN-treated cancer cells show altered mitochondrial metabolism and increased apoptosis (Liu et al, 2013). In addition, MSTN has been suggested to inhibit brown fat differentiation (Kim et al, 2012;Braga et al, 2013;Singh et al, 2014) and affect bone development (Kaji, 2016;Oestreich et al, 2016). MSTN also appears to play a role in fibrosis (Biesemann et al, 2015).…”