Characterization of muscle in OI Model mice

Abstract only availableOsteogenesis imperfecta (OI) is a congenital connective tissue disorder characterized by decreased bone mineral density and increased bone fragility and susceptibility to fracture. In addition to skeletal fragility, patients with OI reportedly have muscle weakness although currently no systematic evaluation of muscle function or morphology in humans or animal models of the disease has been performed. Normal type I collagen is coded for two genes located on different chromosomes: COL1A1 and COL1A2. The oim/oim mouse is homozygous for a null mutation in the COL1A2 gene and is a phenocopy of human type III OI (severe disease phenotype). Heterozygous mice (oim/+) harbor the null mutation in only one allele of the COL1A2 gene and model human patients with type I OI (mild disease phenotype). We wanted to determine whether the reported muscle weakness in OI patients is due to a muscle pathology. We analyzed the muscle mass, fiber morphology, and cross-sectional area of muscles fibers of the hind limb muscles (quadriceps, gastrocnemius, plantaris, tibialis anterior and soleus), as well as the fiber type composition of the soleus muscle of wildtype (wt), heterozygous (oim/+), and homozygous (oim/oim) mice. Our results demonstrate that the muscle mass/body mass, fiber morphology, cross-sectional area of hindlimb muscles, as well as fiber type composition of the soleus muscle of oim, oim/+ relative to wt (+/+) mouse muscles were not significantly different between the genotypes. We correlated our morphologic findings with a functional contractile assay and determined that muscle tension-force generation and nerve conduction are not impaired in oim/oim or oim/+ mice. These findings suggest that oim and oim/+ mice do not have inherent muscle pathology. This knowledge is important in our ultimate understanding of skeletal muscle in OI model mice and ultimately, humans with this disease.Life Sciences Undergraduate Research Opportunity Progra

Do type I collagen defects that cause Osteogenesis Imperfecta result in an inherent muscle pathology? [abstract]

Abstract only availableOsteogenesis imperfecta (OI) is a congenital connective tissue disorder characterized by decreased bone mineral density and increased bone fragility and susceptibility to fracture. In addition to skeletal fragility, patients with OI reportedly have muscle weakness, although currently no systematic evaluation of muscle function or morphology in humans or animal models of the disease has been performed. Normal type I collagen is coded for by two genes located on different chromosomes: COL1A1 and COL1A2. The oim/oim mouse is homozygous for a null mutation in the COL1A2 gene and is a phenocopy of a human type III OI (severe disease phenotype). Heterozygous mice (oim/+) harbor the null mutation in only one allele of the COL1A2 gene and model human patients with type I OI (mild disease phenotype). One of our aims is to characterize and determine muscle mass and cross-sectional area of hind limb muscle fibers in wild type (+/+), heterozygous (oim/+), and homozygous (oim/oim) mice. We analyzed muscle mass, fiber morphology, cross-sectional area of hindlimb muscles, as well as fiber type composition of the soleus muscle of oim, oim/+ relative to +/+ mouse muscles and determined that significant differences do not exist between genotypes. We also determined that there is no evidence of necrosis, degeneration, regeneration, hypertrophy or atrophy in hindlimb muscles of oim/oim and oim/+ mice. We correlated our morphologic findings with a functional contractile assay and determined that muscle tension-force generation and nerve conduction are not impaired in oim mice. These findings suggest that oim and oim/+ mice do not have inherent muscle pathology. This knowledge is important in our ultimate understanding of skeletal muscle in OI model mice and ultimately, humans with this disease.Biochemistry Departmen

Characterization of skeletal muscle in mouse models of osteogenesis imperfecta and myostatin deficiency

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on August 3, 2010).Vita.Thesis advisor: Charlotte Phillips."May 2010"Ph. D. University of Missouri-Columbia 2010.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Osteogenesis imperfecta (OI) is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from mutations in the pro[alpha]1(I) or pro[alpha]2(I) collagen genes. Muscle weakness is an often-reported, little-investigated concern of patients with OI. We examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim and +/G610C) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. Four month old oim/oim mouse muscles were generally smaller, had weaker muscles and an inability to sustain Po for the 300 ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. Though four month old +/G610C mice had significant changes in the relative wet weights of the Q muscle (males) and S and G muscles (females) compared with same sex wt mice, their muscles were not weaker compared to their same sex wildtype (wt) counterparts. We next investigated the effects of exercise on skeletal muscle and bone. We found that oim/oim mice could not tolerate impact exercise but that +/oim mice responded similarly to exercise as wt mice, with modest improvements in bone biomechanical integrity. Lastly, we characterized the skeletal muscle in male and female myostatin (MSTN) deficient mice. Absence of functional MSTN during fetal development results in adult skeletal muscle hypertrophy and hyperplasia. Visible pathology in male Mstn -/- mice and decreased contractile strength relative to increased muscle weight suggest MSTN loss results in muscle impairment which is dose, sex and muscle dependent.Includes bibliographical references

Effects of exercise on bone parameters in the oim mouse model [abstract]

Abstract only availablePrevious studies have shown that mechanical loading on the skeleton acts as an anabolic stimulus, including changes in bone geometry, bone mineral density, and mechanical properties. Increases in these properties may improve bone quality as seen by increased bone density following sustained physical activity, and the increase may be due to increased muscle contraction. This study is aimed at examining the effects of exercise on the skeleton of the oim mouse model. The oim mouse model produces defective type I collagen, the most abundant structural protein in the body. The oim mouse has a phenotype similar to human type III osteogenesis imperfecta (OI), including fractures, cortical thinning, and bowing of long bones. Current therapies for OI have been marginally successful and can be painful and invasive with significant recovery times. Data from this study may aid in development of non-invasive treatments via target exercise and muscle training for OI and other bone diseases such as osteoporosis. This project served as a pilot study to test the effect of swimming on the oim mouse model. Mice were divided into two groups: swim and control. The mice in the swim group swam for 30 minutes/day, 5 days/week for 6 weeks against a water current to ensure constant movement. At the end of the 6 week exercise regimen, mice were euthanized and their leg bones removed. The right femur and tibia were subject to microCT to obtain geometric parameters before undergoing torsional loading to failure to assess bone biomechanics. The left femur underwent the hydroxyproline assay to measure collagen content in bone. Data thus far has shown that in the control group, oim mice have reduced femoral biomechanical integrity and collagen content as compared to wildtype mice. Although the sample size is small, swimming appears to improve the biomechanical integrity of oim femora, although they did not attain wildtype levels. Future studies will be designed to determine if an extended exercise regimen of 8 weeks or if high impact exercise like running will induce more dramatic effects on bone.Life Sciences Undergraduate Research Opportunity Progra