published_or_final_version / Chinese / Doctoral / Doctor of Philosophy

Long-term, high protein diets at 35% of energy may have implications in bone biology. The objective of this study was to comprehensively examine whether a high mixed protein diet at the 35% energy level can be deemed safe with respect to long-term bone health. Eighty female Sprague-Dawley rats were randomized to receive 4, 8, 12, or 17 months of a control (15% of energy as protein) or the high protein diet (35% of energy). Statistical analyses of biochemical, biomechanical, morphological, microarchitectural, and densitometric examinations using a 2-way factorial ANOVA with interaction revealed that elevated protein consumption had no negative consequences to bone health. High protein fed rats had increased lean body mass and decreased body weight and body fat. Thus preliminary results suggest that protein consumption at 35% of energy has a positive effect on body weight and does not hinder the mechanical abilities of bone.

Skeletal development is a complex event that requires a delicate balance between bone formation and bone resorption. Multiple transcription factors expressed in the bone-forming cells, osteoblasts, play crucial roles during the process of bone formation. Among them, ATF4 (Activating Transcription Factor 4) is a basic domain-leucine zipper transcriptional activator that is responsible for osteoblast differentiation, osteoblast-specific genes expression, synthesis of type I collagen, and osteoclast differentiation. Mice deficient for ATF4 are runted and exhibit severe skeletal dysplasia. Our laboratory has discovered Factor Inhibiting ATF4-mediated Transcription (FIAT), whose name was coined for its interaction with ATF4 and subsequent repression of ATF4-mediated osteocalcin gene transcription. FIAT is a leucine zipper nuclear molecule lacking a basic domain for DNA binding. We hypothesize that FIAT suppresses the bone-forming activities of osteoblasts by interacting with ATF4 and thereby blocking ATF4 attachment to the DNA to mediate downstream signalling pathways. To prove this hypothesis, we monitored the expression profiles of FIAT in parallel with ATF4 during osteoblastogenesis. Mechanism of FIAT repression of ATF4 was investigated through structure-function and mutation analysis. The physiological significance of FIAT expression in osteoblasts was studied through silencing FIAT in osteoblasts by RNA interference, as well as through characterization of two genetic mouse models: FIAT transgenic mice which overexpress FIAT in osteoblasts, and osteoblast-specific FIAT knockout mice. These studies showed that FIAT and ATF4 are co-expressed in osteoblasts, and that FIAT inhibition of matrix mineralization requires dimerization with ATF4 through the second leucine zipper. Furthermore, transgenic mice overexpressing FIAT exhibited osteopenia whereas FIAT knockout mice showed enhanced bone formation. These results support our hypothesis and demonstrate that FIAT is a key transcriptional repressor that modulates osteoblast function.

The effect of zinc deficiency on the growth promoting effect of circulating IGF-I and the direct growth effect of GH on long bone growth were investigated. Food intake was decreased by lack of zinc in the diet. Tissue zinc content and plasma alkaline phosphatase activity were reduced by zinc deficiency. Systemic administration of human IGF-I increased the body weight, tail length and tibia epiphyseal cartilage width of control animals. This somatogenic action was impaired by zinc deficiency, as evidenced by continued weight loss, no increase in tail length and decreased tibial epiphyseal cartilage width of zinc deficient animals. Unilateral arterial infusion of GH increased the tibial epiphyseal width of the treated limb but not of the non-treated limb in control rats. However, no difference was found between the infused and the non-infused limb of zinc deficient animals, suggesting the occurrence of GH resistance on long bone growth in zinc deficiency. We conclude that zinc deficiency inhibits the growth promoting action of circulating IGF-I and the direct growth effect of GH on long bone growth.

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The role of vitamin K in the blood clotting cascade has been well documented. Vitamin K has recently been implicated in improving bone health. The current studies were conducted to determine the effects of vitamin K in diets with and without mycotoxin contaminated corn on growth performance, bone characteristics, and related blood metabolites in pigs from weaning to market. Menadione sodium bisulfite complex (MSBC, 33% vitamin K) was chosen as the source of supplemental vitamin K because it is the most common form fed to swine. Vitamin K was tested at 0, 0.5, and 2.0 ppm in a corn-soybean meal based diets on two generations of pigs to evaluate any time and dose responses. The first generation of pigs was subjected to mycotoxin contaminated corn in the nursery phase to test for any interactions between the toxins and vitamin K. The addition of 0.5 ppm vitamin K reduced (P < 0.0001) prothrombin time. No additional decrease in prothrombin time was detected when increasing vitamin K inclusion from 0.5 to 2.0 ppm. With regard to growth performance, daily gain, feed intake, and feed efficiency were unaffected (P > 0.10) by supplemental vitamin K. However, pigs fed mycotoxin contaminated corn ate less (P = 0.005) and grew slower (P = 0.015) compared to those receiving good corn. The addition of vitamin K did not alleviate the negative growth effects in response to corn type. Vitamin K did not affect bone characteristics (P > 0.10), blood Ca (P > 0.05) or OC (P > 0.10). Other than blood clotting it does not appear that dietary vitamin K provides any additional benefits at these levels of inclusion and stages of swine production.

Exercise is known to have a long-term benefit on bone mass in children, but little is known about the underlying mechanisms. The purpose of this investigation was to determine the acute effect of exercise on bone metabolism in pre-pubertal children. Biochemical markers of bone formation were measured in 4 male and 4 female children, 8 to 11 years of age. Each subject performed 50 vertical jumps. Serum osteocalcin and C-telopeptide of type I collagen (CTx), were determined prior to exercise and at 24 and 72 hours post exercise as indicators of bone formation and bone resorption. Osteocalcin concentration was 8.20 ± 3.65 ng•mL"' before exercise, and was 7.1 ± 3.7 ng•mL-' and7.4 ± 3.7 ng•mL-' at 24 hours and 72 hours post exercise, respectively (P > 0.05). CTx concentrations were 11632 ± 4093 pmol•L-' before exercise, and was 9831 ± 3159 pmol•L-' at 24 hours and 9722 ± 2426 pmol•L7' at 72 hours post exercise (P > 0.05). In conclusion an acute bout of ballistic exercise appears to have no effect on bone metabolism in pre-pubertal children. / School of Physical Education

Osteoporosis is a significant public health problem for individuals over age 50 (55% are at risk), particularly for women. A key preventive strategy is increasing peak bone mass in youth. Limited information exists on the role that competitive sport activities can play in developing bone mass. Volleyball is a popular sport for girls and involves high impact activity and plyometric training. The purpose of the study was to compare bone mineral density (BMD) between high school and college competitive volleyball players to age matched controls. Relationships between BMD and age, and years of competitive play were also analyzed. The calcium intake, and time spent jumping in practice (volleyball players only) for each group were also assessed. Subject inclusion criteria were: no eating disorders, not amenorrhoeic, did not use calcium supplements (doctor recommended). The volleyball players followed the criteria above and played volleyball >7 months in a year. Subjects were 13 high school volleyball players (HSVB), 10 high school non-athletes (HSN), and 13 college volleyball players (CVB), and 13 college nonathlees (CN). The mean (+ SD) age, weight, body fat percentage, calcium intake, and years of competitive volleyball for the HSVB players were 16.2 + 1.3 yr, 67.5 + 8.0 kg, 27.2 ± 5.3 %, 1269.7 ± 581.7 mg, and 7.2 ± 1.2 yr. and for the CVB players were 19.5 + 1.0 yr, 74.2 ± 9.2 kg, 28.4 ± 4.7 %, 1059.6 ± 462.2 mg, and 8.5 ± 2.3 yr. respectively. The mean (+SD) age, weight, body fat percentage, and calcium intake for the HSN 16.2 ± 1.3 yr, 66.8 ± 12.4 kg, 34.7 + 6.1 %, and 857.9 + 469.5 mg and for the CN were 19.5 ± 1.0 yr, 73.9 + 9.1 kg, 40.1 + 4.4 %, and 1216.4 + 551.9 mg. Dual energy x-ray absorptiometry (DEXA) was used to determine the body composition and BMD at the following regions: AP spine, dual femur, and total body. The only significant descriptive difference was in percent body fat (P>0.05-0.01). The significant difference (P>0.01) between the athletes and non-athletes occurred in the AP spine (1.38 + 0.1 g.cm-2 and 1.20 ± 0.1 g•cm-2), dual femur (1.22 + 0.1 g•cm 2 and 1.05 ± 0.1 g•cm-2), and total body measurements (1.26 ± 0.1 g•cm 2 and 1.16 ± 0.1 ?cm-2). The athleticism and age was not significant for the BMD in the AP spine, total body, and dual femur. Likewise, the correlations between years playing volleyball and jumping in practice were not significant. The correlation between calcium intake in volleyball players and non-athletes showed no significant difference. In conclusion BMD is higher in volleyball players compared to non-athletes however there was no difference between the college and high school volleyball players. / School of Physical Education, Sport, and Exercise Science

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