Bone acquisition in healthy young females is reciprocally related to marrow adiposity.

CONTEXT: Considerable evidence indicates that osteoblasts and adipocytes share a common progenitor cell in the bone marrow that is capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation. OBJECTIVE: The purpose of this study was to examine the relation between bone acquisition and changes in marrow adiposity. DESIGN: This was a longitudinal study. OUTCOME MEASURES AND SUBJECTS: Computed tomography measurements of femoral cortical bone area (CBA), cross-sectional area (CSA), and marrow density, and dual-energy x-ray absorptiometry (DXA) measurements of total body fat and lean mass (LM) were obtained in 39 healthy females (15-20 yr of age) at baseline and 18-24 months later. RESULTS: Marrow adiposity was inversely related to CBA at baseline and follow-up (r = 0.39 and 0.33; P = 0.015 and 0.039, respectively) but was not associated to CSA (r = 0.19 and 0.17; P = 0.24 and 0.32, respectively). The association between marrow fat and CBA persisted, even after controlling for body mass and DXA values of LM and femoral CSA. Gains in CBA during the course of the study were related to decreases in marrow fat (r = 0.41; P = 0.009), a relation that persisted, even after accounting for changes in bone size. Marrow fat was not associated to anthropometric measures or DXA values of body fat and LM (all r's between -0.15 and 0.19; P > 0.05). CONCLUSIONS: Bone acquisition in the appendicular skeleton of healthy young females is inversely related to changes in marrow adiposity. These results provide support for the growing body of evidence indicating an inversely coupled relationship between osteogenesis and adipogenesis in the skeleton.

Probing DNA- and ATP-mediated conformational changes in the MutS family of mispair recognition proteins using deuterium exchange mass spectrometry.

We have performed deuterium exchange mass spectrometry (DXMS) to probe the conformational changes that the bacterial MutS homodimer and the homologous eukaryotic heterodimer Msh2-Msh6 undergo when binding to ATP or DNA. The DXMS data support the view that high affinity binding to mispair-containing DNA and low affinity binding to fully base-paired DNA both involve forming rings by MutS protein family dimers around the DNA; however, mispair binding protects additional regions from deuterium exchange. DXMS also reveals two distinct conformations upon binding one or two ATP molecules and that binding of two ATP molecules propagates conformational changes to other regions of the protein complexes. The regions showing major changes in deuterium exchange upon ATP binding tend to occur in regions distinct from those involved in DNA binding, suggesting that although communication occurs between DNA and nucleotide binding, sliding clamps formed by binding both ATP and mispairs could result from the simultaneous action of two independent conformational changes.

Vitamin D status and its relation to muscle mass and muscle fat in young women.

CONTEXT: Vitamin D insufficiency has now reached epidemic proportions and has been linked to increased body fat and decreased muscle strength. Whether vitamin D insufficiency is also related to adipose tissue infiltration in muscle is not known. OBJECTIVE: The objective of the study was to examine the relationship between serum 25-hydroxyvitamin D (25OHD) and the degree of fat infiltration in muscle. DESIGN: This was a cross-sectional study. OUTCOME MEASURES AND SUBJECTS: Measures were anthropometric measures, serum 25OHD radioimmunoassay values, and computed tomography (CT) values of fat, muscle mass, and percent muscle fat in 90 postpubertal females, aged 16-22 yr, residing in California. RESULTS: Approximately 59% of subjects were 25OHD insufficient (< or = 29 ng/ml), of which 24% were deficient (< or = 20 ng/ml), whereas 41% were sufficient (> or = 30 ng/ml). A strong negative relationship was present between serum 25OHD and CT measures of percent muscle fat (r = -0.37; P < 0.001). In contrast, no relationship was observed between circulating 25OHD concentrations and CT measures of thigh muscle area (r = 0.16; P = 0.14). Multiple regression analysis indicated that the relation between 25OHD and muscle adiposity was independent of body mass or CT measures of sc and visceral fat. Percent muscle fat was significantly lower in women with normal serum 25OHD concentrations than in women with insufficient levels and deficient levels (3.15 +/- 1.4 vs. 3.90 +/- 1.9; P = 0.038). CONCLUSIONS: We found that vitamin D insufficiency is associated with increased fat infiltration in muscle in healthy young women.

Adiposity predicts carotid intima-media thickness in healthy children and adolescents.

OBJECTIVE: To examine whether anthropometric measurements, blood pressure (BP), fasting total cholesterol, and low-density lipoprotein are related to ultrasound measures of carotid intima-media thickness (CIMT) in children and teenagers with no known risk factors for cardiovascular disease. STUDY DESIGN: This cross-sectional study included 599 subjects, 6 to 20 years of age (292 males, 307 females; 224 Hispanics, 210 European-Americans, 126 African-Americans, and 39 Asian-Americans) whose body mass index, waist circumference, BP, lipid profiles, and values for CIMT were determined. RESULTS: Measures of CIMT were significantly greater in males than females (P=.006) and in African-Americans when compared with other ethnic groups (all P < .05). There were no relations between age, diastolic BP, or fasting levels of triglycerides, total cholesterol, or low-density lipoprotein values and CIMT measures, regardless of sex or ethnic background. Stratified multiple regression analysis indicated that body mass index and waist circumference independently predicted CIMT in both males and females, even after controlling for age, weight, BP, fasting lipid levels, and ethnic background. CONCLUSION: Increased body mass and adiposity are associated with increased intima-media thickness in children and teenagers. This association is present in children not considered overweight, underscoring the need for the continued promotion of adequate nutritional and physical exercise behavior during childhood.

Reciprocal relations of subcutaneous and visceral fat to bone structure and strength.

CONTEXT: Increased body fat is a risk factor for cardiovascular and metabolic disease, yet it is uncertain whether obesity protects against osteoporosis or adiposity is harmful to bone. OBJECTIVE: The aim of the study was to assess whether the pattern of adipose tissue deposition influences bone structure and strength. DESIGN: The relations between sc and visceral adiposity and the cross-sectional dimensions and polar and principal moments of the femur in 100 healthy women ages 15 to 25 years were obtained using computed tomography. RESULTS: Multiple linear regression analyses indicated that, after adjusting for leg length and thigh musculature, both sc and visceral fat had strong and independent associations with femoral cross-sectional area, cortical bone area, principal moment maximum, principal moment minimum, and polar moment (all P values < 0.03). However, whereas sc fat had a positive predictive value with all femoral bone phenotypes, a similar but negative effect was observed between visceral fat and these measures (all P values < 0.01). CONCLUSIONS: We found that visceral and sc fat have opposite effects on the appendicular skeleton; whereas sc fat is beneficial to bone structure and strength, visceral fat serves as an unique pathogenic fat depot.

A conserved MutS homolog connector domain interface interacts with MutL homologs.

Escherichia coli MutS forms a mispair-dependent ternary complex with MutL that is essential for initiating mismatch repair (MMR) but is structurally uncharacterized, in part owing to its dynamic nature. Here, we used hydrogen/deuterium exchange mass spectrometry and other methods to identify a region in the connector domain (domain II) of MutS that binds MutL and is required for mispair-dependent ternary complex formation and MMR. A structurally conserved region in Msh2, the eukaryotic homolog, was required for formation of a mispair-dependent Msh2-Msh6-Mlh1-Pms1 ternary complex. These data indicate that the connector domain of MutS and Msh2 contains the interface for binding MutL and Mlh1-Pms1, respectively, and support a mechanism whereby mispair and ATP binding induces a conformational change that allows the MutS and Msh2 interfaces to interact with their partners.