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Bone

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Overview

Representative graphs showing femur torque versus angular displacement for wildtype and oim/oim femora at four months of age. Torsional ultimate strength (Tmax) is the maximum applied torque required to fracture the bone. Energy to failure (U; shaded area) is the amount of strain energy the bone can absorb prior to fracture. The insert illustrates a least-squares fit line to data from 5 to 10 Nmm with the torsional stuffness (Ks) derived from the slope of this line. Image courtesy of Stephanie Carleton, Ph.D. Click here for larger image.

A Combinatorial Approach of Exercise and Myostatin Inhibition to Enhance Compromised Bone (Postdoctoral Fellowship)

A Combinatorial Approach of Exercise and Myostatin Inhibition to Enhance Compromised Bone (Postdoctoral Fellowship)

Exercise studies using mice with osteogenesis imperfecta (the brittle bone disease) could help humans who have the disease and astronauts who lose bone density on space missions. Researchers hope to learn whether exercise, such as walking on a treadmill, will improve bone density and strength in this mouse and others. Photo by Shane Epping, Mizzou Wire at the University of Missouri. Click here for larger image.

Principal Investigator:
Stephanie M. Carleton, Ph.D.

Organization:
University of Missouri-Columbia

Long-duration spaceflight poses many health risks for human explorers. Astronauts in microgravity are susceptible to developing weaker bones, which is also a serious problem on Earth for those who suffer from osteoporosis and other bone diseases. NSBRI Postdoctoral Fellow Dr. Stephanie M. Carleton has developed a research project to study how the absence of myostatin — a negative regulator of muscle growth — impacts the bone quality of mice with brittle bones, which models the segment of the human population with osteoporosis. Carleton’s hypothesis is that the muscle mass in the mice with the mutation and osteoporosis-like symptoms will increase during exercise, leading to stronger bones due to the added stress to the bones from the larger muscles. This research could lead to effective bone loss countermeasures during long-duration spaceflight and improved treatments for patients suffering from bone loss.

NASA Taskbook Entry


Technical Summary

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder caused by mutations in one of the two type I procollagen genes, COL1A1 and COL1A2. The resulting phenotype is short stature, bone deformity and numerous lifetime fractures. The oim/oim model mice are the most widely studied mouse model of OI. Oim/oim mice are homozygous for a null mutation in the COL1A2 gene of type I collagen and have significantly reduced femoral biomechanical strength and increased femoral stiffness as well as altered bone mineral composition. Heterozygous mice (+/oim) have a phenotype intermediate to oim/oim and wildtype (Wt) mice. G610C OI model mice represent a new mouse model of OI based on a large Amish population in which 64 individuals all carry the same COL1A2 mutation.

Bone is inherently mechanosensitive, responding and adapting to its mechanical environment. Bone formation occurs in response to high mechanical loads, often changing its geometry to strengthen the skeleton. The largest physiological loads bones typically experience are from muscles with bone strength directly proportional to muscle mass.

Myostatin (mstn) is a member of the transforming growth factor- (TGF-) super family and is a negative regulator of skeletal muscle growth. When the myostatin protein is missing or non-functional, the result is increased muscle growth with a concomitant increase in bone strength. Recently a completely myostatin-deficient child was described whose quadriceps muscles were 7.2 standard deviations above normal but without any detrimental health consequences. Myostatin-deficient mice have a similar phenotype: increased muscle mass and bone strength compared to Wt mice. Previous studies demonstrated that mice completely deficient for myostatin (mstn/mstn) have a 40 percent increase in quadriceps muscle mass, an 11 percent increase in bone mineral density and a 20 percent increase in radial ultimate force relative to Wt mice. When mstn/mstn mice were subjected to treadmill exercise, radial ultimate force improved by an additional 17 percent. Exercise has also been shown to be beneficial for human patients at an increased risk for fracture (i.e., osteoporosis, osteogenesis imperfecta).

Based on these previous reports, this project was designed to determine if a combination of exercise and myostatin haploinsufficiency could improve the bone strength in mice with compromised bone (+/oim and G610C OI).

Specific Aims

  1. Determine if +/oim and G610C OI mice are able to tolerate and respond to treadmill exercise.
  2. Determine if myostatin haploinsufficiency will ameliorate the bone phenotype of +/oim and G610C OI mice.
  3. Determine if a combination of exercise coupled with myostatin haploinsufficiency will increase muscle mass and bone strength in +/oim and G610C OI mice.
The long-term goal of this project is to determine if a combination of these two therapies may be additive, further improving the bone phenotype beyond either therapy alone. This combination would represent a novel treatment approach for OI patients, astronauts returning from microgravity, bed-rest patients and others with compromised bones.

Preliminary data demonstrates the reduction in bone strength seen in female +/oim animals was partially rescued when those mice either underwent treadmill exercise or were also haploinsufficient for the myostatin protein (+/mstn). Treadmill exercise did not appear to impact femoral geometry. However, modest improvements were seen in femoral torsional ultimate strength and energy to failure in both Wt and +/oim mice, though these improvements were not significant. Treadmill exercise did significantly reduce whole bone and material stiffness in both Wt and +/oim mice. Curiously, treadmill exercise did not appear to be beneficial for male Wt or +/oim mice. Myostatin haploinsufficiency marginally improved femoral torsional ultimate strength and energy to failure in +/oim mice, though not significantly. Myostatin haploinsufficiency did significantly reduce whole bone and material stiffness in +/oim mice. Taken together, this data indicates that both treadmill exercise and myostatin deficiency has the potential to improve bone strength and reduce stiffness in +/oim mice with compromised bone.

In order to complete this study, additional female +/oim mice will be evaluated to assess the impact of myostatin haploinsufficiency on both muscle size and bone strength and stiffness. Additionally, the same studies will be performed on male +/oim mice to determine if a gender difference exists in the ability of the bone to respond to myostatin haploinsufficiency. Male and female G610C OI mice will also be evaluated for their ability to respond to treadmill exercise. The potential impact of maternal myostatin haploinsufficiency on the muscle size and bone strength of the offspring will also be evaluated. Finally, +/oim mice of both genders that are also haploinsufficient for myostatin will be subjected to treadmill exercise to determine if exercise coupled with myostatin haploinsufficiency further improves bone strength in +/oim mice.


Earth Applications

Muscle atrophy and bone loss are both associated with the weightlessness experienced by astronauts, but these are also widespread health concerns on Earth. As a person ages, muscle use tends to decrease. With disuse, muscle atrophy increases and bone strength decreases with a concomitant increase in fracture risk. While it has long been known that exercise decreases muscle atrophy and fracture risk while increasing bone strength, the role that myostatin haploinsufficiency may play in further augmenting the positive physiological effects of exercise is not known. This study is designed to determine the effects of exercise on the bone strength in both normal mice and mice with compromised bone whose clinical outcome mimics that seen in osteoporosis patients. The study will also look at what impact, if any, myostatin haploinsufficiency has on bone strength, muscle physiology and muscle strength in both normal mice and mice with compromised bone. Additionally, this study will determine if a combination of exercise and myostatin haploinsufficiency will prevent both muscle atrophy and bone loss. At the completion of this study, we will have determined whether a pharmacological approach of myostatin inhibition should be pursued, along with the inclusion of exercise, to potentially ameliorate the muscle atrophy and bone loss often seen as a consequence of a sedentary lifestyle.

This project's funding ended in 2010