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Articles by J Ulloor
Total Records ( 3 ) for J Ulloor
  F. R Sattler , C Castaneda Sceppa , E. F Binder , E. T Schroeder , Y Wang , S Bhasin , M Kawakubo , Y Stewart , K. E Yarasheski , J Ulloor , P Colletti , R Roubenoff and S. P. Azen
 

Context: Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat.

Objectives: We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men.

Design, Setting, and Participants: One hundred twenty-two community-dwelling men 70.8 ± 4.2 yr of age with body mass index of 27.4 ± 3.4 kg/m2, testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (≤167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 µg/kg · d) for 16 wk.

Main Outcome Measures: Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted.

Results: Total lean body mass increased (1.0 ± 1.7 to 3.0 ± 2.2 kg) as did appendicular lean tissue (0.4 ± 1.4 to 1.5 ± 1.3 kg), whereas total fat mass decreased by 0.4 ± 0.9 to 2.3 ± 1.7 kg as did trunk fat (0.5 ± 0.9 to 1.5 ± 1.0 kg) across the six treatment groups and by dose levels for each parameter (P ≤ 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 ± 34 to 35 ± 31% (P < 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 ± 137sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 ± 14 and 8 ± 8 mm Hg, respectively. Other predictable adverse events were modest and reversible.

Conclusions: Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.

  R Jasuja , J Ulloor , C. M Yengo , K Choong , A. Y Istomin , D. R Livesay , D. J Jacobs , R. S Swerdloff , J Miksovska , R. W Larsen and S. Bhasin
 

Ligand-induced conformational perturbations in androgen receptor (AR) are important in coactivator recruitment and transactivation. However, molecular rearrangements in AR ligand-binding domain (AR-LBD) associated with agonist binding and their kinetic and thermodynamic parameters are poorly understood. We used steady-state second-derivative absorption and emission spectroscopy, pressure and temperature perturbations, and 4,4'-bis-anilinonaphthalene 8-sulfonate (bis-ANS) partitioning to determine the kinetics and thermodynamics of the conformational changes in AR-LBD after dihydrotestosterone (DHT) binding. In presence of DHT, the second-derivative absorption spectrum showed a red shift and a change in peak-to-peak distance. Emission intensity increased upon DHT binding, and center of spectral mass was blue shifted, denoting conformational changes resulting in more hydrophobic environment for tyrosines and tryptophans within a more compact DHT-bound receptor. In pressure perturbation calorimetry, DHT-induced energetic stabilization increased the Gibbs free energy of unfolding to 8.4 ± 1.3 kcal/mol from 3.5 ± 1.6 kcal/mol. Bis-ANS partitioning studies revealed that upon DHT binding, AR-LBD underwent biphasic rearrangement with a high activation energy (13.4 kcal/mol). An initial, molten globule-like burst phase (k ~30 sec–1) with greater solvent accessibility was followed by rearrangement (k ~0.01 sec–1), leading to a more compact conformation than apo-AR-LBD. Molecular simulations demonstrated unique sensitivity of tyrosine and tryptophan residues during pressure unfolding with rearrangement of residues in the coactivator recruitment surfaces distant from the ligand-binding pocket. In conclusion, DHT binding leads to energetic stabilization of AR-LBD domain and substantial rearrangement of residues distant from the ligand-binding pocket. DHT binding to AR-LBD involves biphasic receptor rearrangement including population of a molten globule-like intermediate state.

 
 
 
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