ABSTRACT Background: Developmental exposure to endocrine disrupting chemical (EDC), such as Bisphenol A (BPA) has been shown to affect the health during early stages in life. Aim: To assess whether developmental low-dose exposure to BPA alters adipocyte distribution and blood lipid levels in Fischer 344 (F344) rats. Method: Pregnant F344 rats were exposed to BPA via their drinking water from gestational day 3.5 throughout lactation. Doses given were one below the current European Food Safety Authority´s preliminary tolerable daily intake (TDI) of 4 µg BPA/kg bw/day, 0.5 [lower dose, Ld] and one equal to the previous TDI; 50 [higher dose, Hd] µg BPA/kg bw/day. Half the offspring was sacrificed at 5, and half at 52 weeks of age. Body weight was registered, and plasma lipid levels were analyzed. Inguinal white adipose tissue (iWAT) was weighed, Oil red O-stained and analyzed histologically. Results: Five-week-old Ld males and females Hd exhibited significantly higher triglyceride levels (31%, p<0.01; 41%,p<0.05, respectively) compared to control. Total cholesterol was borderline significantly increased (9%, p=0.0554) in 5-week-old Ld males, compared with control. Adipocyte cell density in the 5-week-old offspring was significantly increased; Ld female rats had increased cell density compared to control and Hd (22% and 23%,p<0.05, respectively), whereas the cell density of Hd males increased compared to Ld (29%, p<0.05). In the 52-week-old offspring blood lipid levels and iWAT cell density were not significantly affected. Conclusions: Results of the present study supports that developmental low-dose BPA exposure contributes to elevated triglyceride levels in 5-week-old animals.

Skeletal muscle possesses remarkable plasticity in responses to altered mechanical load. An established murine model used to increase mechanical load on a muscle is the surgical removal of the gastrocnemius and soleus muscles, thereby placing a functional overload on the plantaris muscle. As a consequence, there is hypertrophic growth of the plantaris muscle. We used this model to study the molecular mechanisms regulating skeletal muscle hypertrophy. Aged skeletal muscle demonstrates blunted hypertrophic growth in response to functional overload. We hypothesized that an alteration in gene expression would contribute to the blunted hypertrophic response observed with aging. However, the difference in gene expression was modest, with cluster analysis showing a similar pattern of expression between the two groups. Despite ribosomal protein gene expression being higher in the aged group, ribosome biogenesis was significantly lower in aged compared with young skeletal muscle in response to the hypertrophic stimulus (50% versus 2.5-fold, respectively). The failure to fully up-regulate pre-47S ribosomal RNA (rRNA) expression in old skeletal muscle undergoing hypertrophy indicated ribosomal DNA transcription by RNA polymerase I was impaired. Contrary to our hypothesis, the findings of the study suggest that impaired ribosome biogenesis was a primary factor underlying the blunted hypertrophic response observed in old skeletal muscle rather than dramatic differences in gene expression. As it appears ribosomal biogenesis may limit muscle hypertrophy, we assessed the dynamic changes in global transcriptional output during muscle hypertrophy, as the majority of global transcription is dedicated to ribosome biogenesis during periods of rapid growth. Metabolic labeling of nascent RNA using 5-ethynyl uridine permitted the assessment of cell type specific changes in global transcription and how this transcription is distributed within the myofiber. Using this approach, we demonstrate that myofibers are the most transcriptionally active cell-type in skeletal muscle, and furthermore, myonuclei are able to dramatically upregulate global transcription during muscle hypertrophy. Interestingly, the myonuclear accretion that occurs with hypertrophy actually results in lower transcriptional output across nuclei within the muscle fiber relative to sham conditions. These findings argue against the notion that nuclear accretion in skeletal muscle is necessary to increase the transcriptional capacity of the cell in order to support a growth response.

Tissues are not solely composed of cells. The extracellular matrix is important for the cell well-being and cell-cell communication. The glycosaminoglycan hyaluronan (HYA) is a widely distributed extracellular matrix (ECM) component. The molecule has prominent physicochemical properties, foremost viscoelastic and osmotic, but participates in many biological processes such as cell migration, proliferation, tissue turnover, wound healing and angiogenesis. HYA is synthesised by either of three different hyaluronan-synthesising enzymes, HAS1-3, and its main ligand is the transmembrane receptor CD44. In the heart and vessels the matrix components are of great importance for endurance and elasticity which are prerequisites for a normal function. The aims of the study were to describe the distribution of HYA and its receptor CD44 in normal cardiovascular tissue and to investigate the ECM composition in myocardial hypertrophy. Normal conditions were studied in a rat model. These studies showed that the tunica adventitia in almost all vessels stained strongly for HYA. The expression in the tunica intima and media on the venous side, differed between the vessels and was almost absent on the arterial side. In the adult animals only minute amounts of CD44 were detected. The expression of both HYA and CD44 was increased in newborn rats. In the heart HYA was unevenly distributed in the interstitium. Strong HYA-staining was seen in the valves and in the adventitia of intramyocardial vessels. Almost no CD44-staining was observed. Notably, there was no obvious difference between newborn and adult animals. In an experimental rat model of pressure-induced cardiac hypertrophy the mRNA-levels of HAS1, HAS2, CD44, basic Fibroblast Growth Factor (FGF-2) and Fibroblast Growth Factor Receptor-1 (FGFR-1) were elevated on day 1 after aortic banding. HAS2, CD44 and FGFR-1 were at basal levels on day 42. The HYA-concentration was significally elevated on day 1. HYA was detected in the interstitium by histochemistry and CD44 was detected mainly in and around the intramyocardial vessels. The HYA-staining was increased in myectomi specimens from patients with HCM compared to controls. HYA was detected in the interstitium, in fibrous septas and in the adventitia of intramyocardial vessels. No CD44 was detected in HCM or in control specimens. Our results indicate that HYA and CD44 play an active role in the maturing vessel tree and that the ECM content of HYA is increased in experimental myocardial hypertrophy and human hypertrophic cardiomyopathy.

No description available.

No description available.

The purpose of the present study was to examine the relationship between exercise induced muscle damage and growth factors during two different modes of exercise. Nine healthy untrained male subjects participated in this study and performed two separate single bouts of isokinetic concentric (Con) and eccentric (Ecc) leg extension exercise on the CYBEX NORMT°". The workload was maintained at 75% of 1 RM for each trial, respectively. The maximum sets of 10 repetitions were performed during the Con trial, and the number was also duplicated during the Ecc trial, with 40 seconds of rest between sets. Serum levels of hGH, creatine kinase (CK), and lactic acid were measured, and the CK level was used to determine the degree of muscle tissue damage. A muscle soreness questionnaire was provided to the subjects to assess the degree of quadriceps muscle soreness following each trial. The EMG activity of the rectus femoris and vastus medialis muscles was recorded during each trial. The results of the present study demonstrated no significant differences in hGH output and CK activity between the exercise trials, although there was a significant different lactic acid response (P < 0.05). However, the Con trial produced significant increases (P < 0.05) in hGH and CK levels above the resting value at the post-exercise times. In fact, the 75% Con trial conducted in this study induced an increase in hGH release (peak: 8.23 ± 3.21 ng/ml) that was 2 X higher than a 120% Ecc trial (peak: 3.8 ± 1.2 ng/mI) of the prior study. The results of the present study demonstrate that a single bout of Con resistance exercise at the same intensity (75% of 1 RM), angular velocity, and ROM as a single bout of Ecc exercise can produce greater increases in hGH output and CK response than its Ecc counterpart. This finding does not support the previous results from this laboratory, showing that Ecc exercise is a stronger promoter of hGH output. However, it suggests that the amount of work performed is an important factor for hGH release because the exercise volume applied in the present study was greater than that of the prior study. The CK response of the subjects in this study, as well as the previous work indicate that hGH output is also dependent on exercise that elicits muscle damage. Therefore, the results of the present study suggest that the mode of exercise, Con vs. Ecc, is not as important as the stress placed on the exercising muscle in order to induce optimal muscle hypertrophy. / School of Physical Education

The human body consists of about 40 % skeletal muscles which control the body’s movement, ability to stand up, force generation, locomotion, heat production and are also the body’s protein reservoir. Muscle mass is controlled by the relationship between protein synthesis and protein degradation. Atrophy, a decrease in muscle mass, can be trigged by disuse, immobilization, inflammation and cancer. Hypertrophy, an increase in muscle mass, can occur after increased mechanical load, high usage and/or anabolic stimulation. The aim of this thesis was to investigate changes in expression and post translational modifications of some factors involved in the regulation of protein synthesis and protein degradation in 6-days denervated atrophic hind-limb muscles (anterior tibial and pooled gastrocnemius and soleus muscles) and in 6-days denervated hypertrophic hemidiaphragm muscle in mice. Protein expression and post translational modifications were studied semi-quantitatively using Western blots with whole muscle homogenates and separated nuclear and cytosolic fractions from both innervated and denervated muscles.  An increase in protein synthesis after denervation in both atrophic and hypertrophic muscles was suggested after studies of factors downstream of mTOR (paper I).  Other results suggest that FoxO1 and MuRF1 (paper II) participate in the tissue remodeling that occurs after denervation. A differential response of MK2 phosphorylation in denervated hypertrophic and atrophic muscles was confirmed (paper III). An increase in phosphorylation of the MK2 substrate Hsp 25 in all denervated muscles studied (paper III) indicates that other factors than MK2 are involved in regulating this phosphorylation. eIF4G phosphorylation at S1108 was investigated (paper IV) and a decrease was observed in atrophic muscle but an increase in hypertrophic muscle. The results in this thesis suggest that there are several factors that control protein degradation and protein synthesis in denervated atrophic and hypertrophic skeletal muscles. This is an intricate labyrinth with many different cell signaling factors, the function of which are still far from fully understood.

Irx5 is a homeodomain transcription factor that negatively regulates cardiac fast transient outward K+ currents (Ito,f) via the KV4.2 gene and is thereby a major determinant of the transmural repolarization gradient. While Ito,f is invariably reduced in heart disease and changes in Ito,f can modulate both cardiac contractility and hypertrophy, less is known about a functional role of Irx5, and its relationship with Ito,f, in the normal and diseased heart. Here I show that Irx5 plays crucial roles in the regulation of cardiac contractility and proper adaptive hypertrophy. Specifically, Irx5-deficient (Irx5-/-) hearts had reduced cardiac contractility and lacked the normal regional difference in excitation-contraction with decreased action potential duration, Ca2+ transients and myocyte shortening in sub-endocardial, but not sub-epicardial, myocytes. In addition, Irx5-/- mice showed less cardiac hypertrophy, but increased interstitial fibrosis and greater contractility impairment following pressure overload. A defect in hypertrophic responses in Irx5-/- myocardium was confirmed in cultured neonatal mouse ventricular myocytes, exposed to norepinephrine while being restored with Irx5 replacement. Interestingly, studies using mice virtually lacking Ito,f (i.e. KV4.2-deficient) showed that reduced contractility in Irx5-/- mice was completely restored by loss of KV4.2, whereas hypertrophic responses to pressure-overload in hearts remained impaired when both Irx5 and Ito,f were absent. These findings suggest that Irx5 regulates cardiac contractility in an Ito,f-dependent manner while affecting hypertrophy independent of Ito,f. On the other hand, Irx5-ablation attenuated calcineurin (Cn)-induced hypertrophy in hearts and cultured cardiomyocytes, suggesting that the effect of Irx5 on hypertrophy involves the Cn-NFAT signalling cascade. Biochemical assessments further revealed that Irx5 can positively mediate Cn-NFAT activities as well as Nfatc3 and Gata4 expression, and interacts with Nfatc3 and Gata4, suggesting the formation of a transcription complex for hypertrophic gene regulation. Taken together, these studies have identified Irx5 as a vital cardiac transcription factor, important for contractile function of the heart by regulating Ito,f, and compensatory hypertrophic response to biomechanical stress in the heart by affecting the Cn-NFAT (and Gata4) signaling pathway.

The purpose of this study was to compare the effects of intra-set rest intervals (ALT) and traditional resistance (STD) training in hypertrophic resistance training. 22 males (25 +/- 5yrs, 179.71 +/- 5.0cm, 82.1 +/- 10.6kg, 13.6 +/- 4.3% fat, 6.5 +/- 4.5yrs training) were matched according to baseline characteristics and randomly assigned to a STD or ALT 12 week hypertrophic training protocol. Body composition, strength (1RM bench and squat); power (60% 1RM bench and squat); and vertical jump were assessed at baseline, 4, 8, and 12 weeks. Muscle biopsy for myosin heavy chain (MHC) was performed pre and post training. A 2 x 4 (Group x Time) ANOVA was used to assess changes in body composition. A 2 x 4 (Group x Time) ANCOVA covaried by baseline performance measures was used to assess differences in strength and power characteristics. A 2 x 2 (Group x Time) ANCOVA covaried for baseline percentage MHC was used to determine differences pre and post training. Both groups experienced increases in FFM with no differences between groups (62.6 +/- 7.9, 63.4 +/- 7.6, 64.2 +/- 7.4, 64.2 +/- 7.5kg; p>0.05). No time effects were noted in percent fat (13.6 +/- 4.3, 14.1 +/- 4.7, 14.0 +/- 4.6, 14.3 +/- 4.6%fat; p>0.05). Increase in FFM was associated with a decrease in MHCIIX, (ALT, -37.9 +/- 24.1%; STD, -23.4 +/- 23.8%; p = 0.001) and an increase in MHCIIA (ALT, 32.0 +/- 28.8%; STD, 25.4 +/- 29.1%; p = 0.001) with no difference between groups. A significant interaction was observed with the ALT group experiencing greater gains in both 1RM bench (STD 104.1 +/- 27.6, 102.7 +/- 29.0, 107.0 +/- 25.3, 113.2 +/- 27.3; ALT 110.9 +/- 20.1, 117.5 +/- 23.7, 120.8 +/- 22.6, 126 +/- 22.8; p<0.05) and 1RM squat (STD 123.3 +/- 39.3, 139.6 +/- 38.8, 160.2 +/- 36.1, 171.8 +/- 34.5; ALT 130.1 +/- 25.1, 152.6 +/- 24.8, 179.8 +/- 24.5, 193.9 +/- 24.2kg; p<0.05). The ALT group experienced greater gains in power in both the bench (STD 560 +/- 122, 541 +/- 105, 572 +/- 122, 593 +/- 135W; ALT 575 +/- 102, 586 +/- 123, 646 +/- 103, 658 +/- 113W; p<0.05) and vertical jump (STD 1378 +/- 237, 1418 +/- 214, 1452 +/- 210, 1470 +/- 215W; ALT 1389 +/- 179, 1434 +/- 152, 1470 +/- 149, 1537 +/- 150W;p<0.05), with gains in squat power approaching significance (STD 625 +/- 245, 704 +/- 233, 723 +/- 227, 830 +/- 232W; ALT 632 +/- 171, 734 +/- 179, 783 +/- 188, 914 +/- 207W; p<0.10). The use of intra-set rest intervals in programs designed to elicit hypertrophy results in greater gains in strength and power with no significant difference in lean mass or MHC composition after a 12 week resistance training program designed to elicit hypertrophy.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1982. / Bibliography: leaves 260-277. / Microfiche. / xiv, 277 leaves, bound ill. 29 cm