Metabolic syndrome (MetS) is a conglomeration of several risk factors for cardiovascular disease, with obesity currently being one of the common causes of disability and death in the United States.1 Underlying the obesity, however, there is metabolic imbalance that could be exacerbating the issue of metabolic syndrome.2 Approximately 34% of adults over 20 years old matched the criteria for metabolic syndrome.3 The risk factors for cardiovascular disease (CVD) associated with metabolic syndrome can, over time, lead to severe CVDs, such as heart failure (HF).4 Metabolic syndrome can also lead to developing metabolic heart disease over time. Understanding the development of cardiac hypertrophy and fibrosis in diet-induced metabolic heart disease allow development of an early treatment of metabolic heart disease (MHD) and HF. This study looked at one potential mediator and its role in cardiac hypertrophy and fibrosis, follistatin-like 3 (FSTL3). FSTL3 is an extracellular antagonist of members of the TGF-β superfamily. The goal of our study was to determine the effect, if any, a knockout of FSTL3 would have on the development of cardiac hypertrophy and fibrosis after a high-fat, high-sucrose diet for five months. FSTL3 knockout mice were given a high-fat, high-sucrose (HFHS) diet for five months. These mice were then sacrificed and their hearts were analyzed for cardiac myocyte hypertrophy and interstitial fibrosis using histological methods. After five months on the HFHS diet, wild-type (WT) mice had cardiac hypertrophy. In FLRG KO mice the diet-induced cardiac hypertrophy was attenuated. WT HFHS-fed mice developed interstitial fibrosis, and FLRG KO HFHS developed more accentuated interstitial fibrosis than WT HFHS diet fed mice. This study is useful in suggesting that FTSL3 contributes to the pathogenesis of cardiac hypertrophy in MHD. FTSL3 may be a useful biomarker for cardiac hypertrophy in patients with suspected MHD, and may be a viable target for therapeutic interventions aimed at decreasing pathologic myocardial hypertrophy.

Metabolic heart disease (MHD) caused by obesity or diabetes is characterized by cardiac hypertrophy, diastolic dysfunction, and fibrosis - a maladaptive remodeling of the extracellular matrix. Though the influence of cardiac fibrosis on the left ventricular diastolic dysfunction has been reported, little is known about the cardiac-specific secreted autocrine, paracrine, or endocrine factors termed "cardiokines" in MHD. Transforming growth factor beta (TGF-b1) is a well-known inducer of cardiac fibrosis. However, the role TGF-b2 in mediating cardiac fibrosis has yet to be described. In addition, follistatin-like 3 (FSTL3), an extracellular inhibitor of activin A and myostatin, is found to be elevated in end-stage heart failure patients and obese individuals. FSTL3 has been suggested as a cardiokine, yet its role in MHD has not been established. To identify cardiokines induced by MHD, two relevant mouse models were employed in this study: the high-fat high sucrose (HFHS) diet feeding model and the cardiomyocyte-specific Fatp1 overexpressing transgenic mouse model. Interstitial fibrosis was observed in both models, accompanied by fibrotic gene expression and anti-fibrotic miR-29 suppression. It was found that Tgf-b1 and Tgf-b2 mRNA were upregulated by 85% and 76%, respectively, in the non-myocytes of 1-month HFHS-fed mice, while Fstl3 was increased by 30% in the myocytes. In contrast, in the FATP1 transgenic animals, Tgf-b2 and Fstl3 were elevated by 3.8-fold and 1.9-fold in the myocytes while Tgf-b1 remained unchanged compared to control animals. The in vitro results tested in NIH3T3 and primary fibroblast cultures indicate that both TGF-b1 and TGF-b2 exerted profibrotic effects via activation of SMAD proteins and collagen synthesis, but FSTL3 did not. Plasma samples collected from patients with metabolic syndrome showed increased FSTL3 levels with strong correlations with cardiac hypertrophy and impaired diastolic function. Overall, this study has demonstrated that TGF-b1 and TGF-b2 are the key profibrotic cardiokines induced in MHD. The study has also revealed the role of FSTL3 as a biomarker for LV hypertrophy induced in MHD. The results presented here should facilitate the development of better diagnosis and treatment for this disease in the future.

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The purpose of this study was to compare the myocardial structure and function among endurance athletes (n.12), powerlifters/steroid users (n=5), powerlifters/non-steroid users (n=6), and sedentary controls (n=4). All subjects had a M-mode echocardiographic examination of their left ventricles under resting conditions. The echocardiographic measurements recorded and analyzed were of the left ventricular posterior wall at diastole and systole, left ventricular internal diameter at diastole and systole, and inter-ventricular septal thickness at diastole and systole. Myocardial function measurements consisting of left ventricle ejection time, left ventricular mass, mean ventricular contractile force, and percent fractional shortening were also recorded and analyzed. A One Way Analysis of Variance was used to analyze the data for statistical significance. A Tukey's HSD post-hoc test was used to determine statistical significance between the groups. A significant difference (p =0.02) was found for inter-ventricular septal thickness during diastole. All three athletic groups had significantly thicker inter-ventricular septa' thickness during diastole as compared to the controls. Power lifters/steroid users had the thickest inter-ventricular septal thickness (18.7 mm), followed by endurance athletes (18.6 mm), and powerlifters/nonsteroid users (16.5 mm). Overall, powerlifters/steroid users had the thickest walls at systole and diastole, while endurance athletes had the greatest internal diameters relative to the size of the left ventricle. Statistically significant differences among the groups were found for all four myocardial functional parameters: left ventricular ejection time (p = 0.03), left ventricular mass (p = 0.002), mean ventricular contractile force of (p 0.0013), and percent fractional shortening (p = 0.05). Power lifters/steroid users had the fastest left ventricular ejection times, largest left ventricular mass, greatest mean ventricular contractile force, and greatest percent fractional shortening. Endurance athletes had the slowest left ventricular ejection times, second largest left ventricular mass, lowest mean ventricular contractile force, and third lowest percent fractional shortening. The results indicated that not all individuals participating in high level endurance or powerlifting training and competition demonstrated complete adaptations in myocardial structure and function. Power lifters/steroid users however, demonstrated myocardial functional adaptations that were significantly different from powerlifters/non-steroid users, endurance athletes, and controls. The results of this study cannot attribute these changes either to the use of large amounts of anabolic steroids, or long-term, high-intensity training and competition in powerlifting. However, the study identified alterations in myocardial functions in powerlifters/steroid users, and contributes to the existing body of knowledge regarding the use of anabolic steroids by athletes. / Graduation date: 1990

Early strength increase with training is normally attributed to neural adaptations but recent evidence suggests that muscle hypertrophy occurs earlier than previously thought. The purpose of this study was to examine the time course of adaptation through 20 days of training and 5 days of detraining. Twenty-two untrained subjects trained one arm every 2nd day for 20 days. Subjects performed isokinetic eccentric biceps training at 90°/s (6 sets of 8 reps). Muscle thickness (reported in cm) via ultrasound, strength (reported in Nm) and muscle activation (electromyography) were measured before, during and after training (9 time points). Muscle thickness increased after 8 days of training (3.66±0.11 to 3.90±0.12; p<0.05) and remained above baseline until the end of training (3.97±0.12). After 5 days of detraining muscle thickness decreased (3.97±0.12 vs. 3.85±0.11; p<0.05), but remained higher than baseline (p<0.05). Muscle thickness did not change significantly in the untrained arm at any time point. Strength in the trained arm decreased after 8 days of training (65.6±4.1 to 57.5±3.5; p<0.05) and remained suppressed throughout the study. Muscle activation amplitude increased after 14 days of training (p<0.05) and remained elevated throughout the study. In conclusion, biceps muscle thickness increases very rapidly with frequent intense eccentric training although this type of training appears to impair strength. These findings provide additional evidence that muscle hypertrophy may occur much faster than has been generally accepted.

Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / School of Physical Education, Sport, and Exercise Science

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.

Early strength increase with training is normally attributed to neural adaptations but recent evidence suggests that muscle hypertrophy occurs earlier than previously thought. The purpose of this study was to examine the time course of adaptation through 20 days of training and 5 days of detraining. Twenty-two untrained subjects trained one arm every 2nd day for 20 days. Subjects performed isokinetic eccentric biceps training at 90°/s (6 sets of 8 reps). Muscle thickness (reported in cm) via ultrasound, strength (reported in Nm) and muscle activation (electromyography) were measured before, during and after training (9 time points). Muscle thickness increased after 8 days of training (3.66±0.11 to 3.90±0.12; p<0.05) and remained above baseline until the end of training (3.97±0.12). After 5 days of detraining muscle thickness decreased (3.97±0.12 vs. 3.85±0.11; p<0.05), but remained higher than baseline (p<0.05). Muscle thickness did not change significantly in the untrained arm at any time point. Strength in the trained arm decreased after 8 days of training (65.6±4.1 to 57.5±3.5; p<0.05) and remained suppressed throughout the study. Muscle activation amplitude increased after 14 days of training (p<0.05) and remained elevated throughout the study. In conclusion, biceps muscle thickness increases very rapidly with frequent intense eccentric training although this type of training appears to impair strength. These findings provide additional evidence that muscle hypertrophy may occur much faster than has been generally accepted.

名古屋大学博士学位論文 学位の種類:博士(リハビリテーション療法学) (課程) 学位授与年月日　平成22年3月25日