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

Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13522-13527. doi: 10.1073/pnas.1607644113. Epub 2016 Nov 7.


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 (Mstntm1Sjl/+) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized that Mstntm1Sjl/+ 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 (Col1a2oim), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of male Col1a2oim/+ offspring from natural mating of Mstntm1Sjl/+ dams to Col1a2oim/+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 Col1a2oim/+ dams to Col1a2oim/+ sires. Finally, increased bone biomechanical strength of Col1a2oim/+ offspring that had been transferred into Mstntm1Sjl/+ 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.

Keywords: bone health; developmental origins of health and disease; fetal programming; myostatin; osteogenesis imperfecta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Biomechanical Phenomena
  • Body Weight
  • Collagen / metabolism
  • Disease Models, Animal
  • Embryo Implantation
  • Female
  • Femur / pathology
  • Femur / physiopathology*
  • Male
  • Mice, Inbred C57BL
  • Muscle Contraction
  • Myostatin / deficiency
  • Myostatin / metabolism*
  • Osteoblasts / metabolism
  • Osteogenesis Imperfecta / blood
  • Osteogenesis Imperfecta / embryology
  • Osteogenesis Imperfecta / physiopathology*
  • Tibia / pathology
  • Tibia / physiopathology


  • Biomarkers
  • Myostatin
  • Collagen