The purpose of this study was to examine the influence of biological maturation on the pattern of fat and carbohydrate metabolism during exercise in early-pubertal (EP), mid-pubertal (MP), and late-pubertal (LP) males. Nine boys, Tanner stage I (EP) (10.3 ±0.9 years), 12 boys, Tanner stage 2/3 (MP) (12.3 ± 1.9 years), and 11 boys, Tanner stage 4/5 (LP) (15.0 ± 0.8 years) were subjects. Maximal aerobic capacity (VO2max) was assessed and, on a separate day, 5, 5-minute exercise bouts on a cycle ergometer at 30, 40, 50, 60, and 70% Of VO2max were performed in a fasted state. Fuel use was calculated at each intensity using steady-state V02 and the respiratory exchange ratio (RER). A one-way ANOVA was used to analyze physical characteristics and maximal exercise responses between groups. A two-way (group x intensity) ANOVA was used to analyze responses during submaximal exercise. Statistical significance was set at p < 0.05. VO2max (ml•kg-l.min 1) was not different between groups. At each intensity, % VO2ma., was similar between groups (p > 0.05). Significant interactions were found for RER, carbohydrate utilization, % fat utilization, and lactate concentration. Post hoc analyses revealed that at all intensities, % fat use and fat oxidation rates were higher and carbohydrate use and carbohydrate oxidation rates were lower in MP versus LP. In comparison, between EP and LP, % fat use was higher and % carbohydrate use was lower at 50-60% of VO2max, while fat oxidation rate was higher in EP versus LP at 40, 50, and 60% of VO2max. The only differences between EP and MP were for % fat and carbohydrate use at 30% of VO2max. Lactate concentrations were also lower in EP and MP than in LP at intensities corresponding to 50, 60, and 70% of VO2m., while no differences were observed between EP and MP at any intensity. The lack of a significant difference in substrate utilization or lactate concentrations between EP and MP at the majority of exercise intensities, suggest that the development of an adult-like metabolic profile occurs in the transition from mid-puberty to late-puberty. / School of Physical Education

Three investigations were conducted using pulsed Doppler echocardiography (PDE) and oxygen consumption to non-invasively determine the relationship between hemodynamic and metabolic variables from rest through submaximal and maximal exercise in early adolescent males. In the first study, interinvestigator and day-to-day variability of cardiac output measurements at rest and during exercise determined by PDE were analyzed in six junior high school age boys. Four Doppler-derived variables (cardiac output, cardiac index, stroke volume, and stroke index) were not different when calculated by independent investigators and showed the same interinvestigator variability from rest through submaximal and maximal exercise as has been reported at rest in previous validation studies. There was a slight but statistically significant increase in the absolute values of the above hemodynamic variables and simultaneously collected metabolic variables during a second identical test conducted approximately nine days later. A faster adjustment to increasing workrates in the second test could explain this latter finding since supine cycle ergometry is not as familiar an activity as more frequently used modes of exercise testing. It is concluded that hemodynamic measurements using PDE exhibit the same acceptable variability throughout exercise as has been previously demonstrated at rest. In the second study, PDE was used to determine rapid serial measurements of cardiac output during a rapid loading supine cycle ergometer exercise test in twenty-two junior high school age boys. These measurements were compared to simultaneoulsy determined measurements of oxygen consumption. Cardiac output adjusted faster to each new workrate than oxygen consumption. Further analysis of these responses revealed that increases in heart rate (as opposed to stroke volume) were responsible for this rapid adjustment. It is concluded that there is an uncoupling and recoupling of these normally closely related hemodynamic and metabolic variables during the transitional periods between increasing levels of steady-state supine exercise. In the final study, gradual loading and rapid loading supine cycle ergometer protocols were compared in fifteen junior high school age boys. Maximal metabolic measurements and heart rate from each test were not different. Maximal PDE-derived measurements of cardiac output, cardiac index, stroke volume, and stroke index were slightly, but significantly, higher in the gradual loading protocol. It is concluded that a more complete adjustment of cardiac output (reflected by stroke volume) to maximal supine exercise occurs in a more gradual loading protocol than in a rapid loading protocol.

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Indiana University-Purdue University Indianapolis (IUPUI) / The class IV alcohol dehydrogenase (ADH7, µ-ADH, σ-ADH) efficiently metabolizes ethanol and retinol. ADH7 is expressed mainly in the upper gastrointestinal tract with no expression in the liver unlike the other ADHs, and is implicated in various diseases including alcoholism, cancer and fetal alcohol syndrome. Genome wide studies have identified significant associations between ADH7 variants and alcoholism and cancer, but the causative variants have not been identified. Due to its association with two important metabolic pathways and various diseases, this dissertation is focused on studying ADH7 regulation and the effects of variants on this regulation using cell systems that replicate endogenous ADH7 expression. We identified elements regulating ADH7 transcription and observed differences in the effects of variants on gene expression. A7P-G and A7P-A, two promoter haplotypes differing in a single nucleotide at rs2851028, had different transcriptional activities and interacted with variants further upstream. A sequence located 12.5 kb upstream (7P10) can function as an enhancer. These complex interactions indicate that the effects of variants in the ADH7 regulatory elements depend on both sequence and cellular context, and should be considered in interpretation of the association of variants with alcoholism and cancer. The mechanisms governing the tissue-specific expression of ADH7 remain unexplained however. We identified an intergenic region (iA1C), located between ADH7 and ADH1C, having enhancer blocking activity in liver-derived HepG2 cells. This enhancer blocking function was cell- and position- dependent with no activity seen in CP-A esophageal cells. iA1C had a similar effect on the ectopic SV40 enhancer. The CCCTC-binding factor (CTCF) bound iA1C in HepG2 cells but not in CP-A cells. Our results suggest that in liver-derived cells, iA1C blocks the effects of downstream ADH enhancers and thereby contributes to the cell specificity of ADH7 expression. Thus, while genetic factors determine level of ADH7 transcriptional activity, iA1C helps determine the cell specificity of transcription.