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, mater… Show more
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Methodsmentioning
confidence: 99%
“…( 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 )…”
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Methodsmentioning
confidence: 99%
“…( 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 )…”
“…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.…”
Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn−/−) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin’s impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease. In this review, we explore myostatin’s role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration. The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.
“…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).…”
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.