The Effect of Congenic Myostatin Inhibition on a Mouse Model of Osteogenesis Imperfecta (OI) Type I/IV

Bone is a dynamic organ in part due to its mechanosensitivity. Muscle mass and force are some of the largest physiological loads that bone experience during its life time, with muscle mass being directly proportional to bone mass. One of the factors regulating muscle mass is myostatin, a member of the TGF‐β superfamily, that acts as a negative regulator of muscle growth. Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a heritable connective tissue disorder characterized by skeletal fragility. A glycine to cysteine substitution in the proα2(I) collagen chain leads to reduced bone mineral density and compromised biomechanical integrity as modeled by the heterozygous G610C (+/G610C) mouse. +/G610C mice model both the genotype and phenotype of 64 affected individuals with mild to moderate type I/IV OI in an Old Order Amish kindred. We investigated the effects of myostatin deficiency on the +/G610C mouse muscle by breeding heterozygote myostatin deficient mice (+/mstn) with +/G610C mice to produce WT, +/mstn, +/G610C, and +/mstn +/G610C mice. After weaning at three weeks of age, mice were weighed weekly until 4 months of age when they were euthanized. After euthanization, 5 hindlimb muscles, the gastrocnemius, quadriceps, tibalis anterior, plantaris, and soleus, were harvested and weighed. Serum was separated from the blood and used to quantify myostatin levels. Serums from +/mstn and +/mstn +/G610C mice demonstrated decreased levels of myostatin as compared to WT and +/G610C mice. +/mstn mice showed increased body weights at four months of age when compared to WT littermates. +/mstn +/G610C mice also had increased body weights as compared to +/G610C littermates, although they did not reach significance. More importantly, however, +/mstn and +/mstn +/G610C mice exhibited significantly increased hindlimb skeletal muscle weights and relative muscle weights as compared to +/G610C mice for the gastrocnemius and quadriceps. These findings demonstrate that myostatin deficiency can lead to increased muscle mass in mice with OI which can potentially lead to increased bone mass and strength.Support or Funding InformationSupported by March of Dimes, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR055907), the Leda J. Sears Trust, the Kansas City Area Life Sciences Institute Patton Trust Research, Inc., and the University of Missouri Research Board Grant. The project described was also supported by the IMSD EXPRESS Fellows Program (or simply the IMSD EXPRESS Program) via grant number R25GM056901 from the National Institute of General Medical Science (NIGMS), a component of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.