Abstract 055: β-Catenin Mediates an Interplay between Genetic Background and Growth-Regulating Effects of Estrogen in the Healthy Heart

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Ba Tiep Nguyen ◽  
Laura C Zelarayan ◽  
Maike Hassenpflug ◽  
Karl Toischer ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Strain Difference ◽  
Wnt Signaling Pathway ◽  
Cross Sectional Area ◽  
Heart Weight ◽  
Mouse Heart ◽  
Sectional Area ◽  
Cross Sectional ◽  
Cardiac Growth ◽  
Protein Levels

In diseased hearts, estrogen (E2) has been shown to exert anti-hypertrophic actions. Little is known about the role of E2 in the healthy heart. Our initial aim was to characterize structurally and molecularly the effects of E2 in the healthy mouse heart. Two-month-old female C57Bl/6J mice were ovariectomized and randomized to an E2-containing or soy-free (control, CON) diet ( n = 17-18/group). The three-month physiological dose of E2 led to a higher relative heart weight compared with CON ( P < 0.001). We also confirmed increased cardiomyocyte cross-sectional area by E2 ( P < 0.01). No activation of the fetal gene program and no fibrosis were observed. Transcriptome analysis revealed induction of growth-related pathways by E2, such as the Wnt signaling pathway ( n = 5/group; adjusted P < 0.05). To further confirm activation of Wnt/β-catenin signaling, we verified increased nuclear β-catenin protein levels by E2 compared with CON ( P < 0.01) and hypothesized that β-catenin mediates the actions of E2. Cardiac deletion of β-catenin blunted the E2 effects on cardiac growth ( n = 13/group). Surprisingly, in wild-type littermates with the background C57Bl/6N, E2 decreased the relative heart weight and cardiomyocyte cross-sectional area compared with CON ( n = 7-11/group; P < 0.001). This was underlain by decreased nuclear β-catenin protein levels by E2 compared with CON ( P < 0.001). Furthermore, E2 increased glycogen synthase kinase 3β (GSK3β) phosphorylation and the endosomal/autophagosomal markers Rab5, Rab7 and LC3-II in C57Bl/6J but not C57Bl/6N mice. Assessing a polymorphism linked to Snap29 , we confirmed higher Snap29 protein levels in C57Bl/6J than C57Bl/6N mice ( P < 0.01). This could lead to distinct regulation of endosomes and could be the potential cause of the strain difference. In conclusion, E2 regulates cardiac growth through β-catenin in a strain-specific manner. Collectively, we identified a molecular mechanism that demonstrates a divergent response of mouse sub-strains to E2.

Abstract P112: Estradiol Induces Physiological Hypertrophic Growth in the Healthy Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Ba Tiep Nguyen ◽  
Hubertus Jarry ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Weight Ratio ◽  
Treated Group ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Mouse Heart ◽  
Cross Sectional ◽  
Hypertrophic Growth ◽  
Protein Levels ◽  
Cycle Regulation

Estradiol-17beta (E2) has been shown to exert anti-hypertrophic actions by either attenuating or blunting the development of left ventricular hypertrophy. However, the vast majority of these studies have been performed in stressed or diseased hearts. Consequently, very little is known about the actions of E2 in the stress- and disease-free heart. The aim of our study was to identify and characterize structurally and molecularly the role of E2 in the healthy heart. Female C57Bl/6J mice were ovariectomized at the age of two months. Mice were randomly assigned into groups feeding on either an E2-containing (n = 19) or soy-free (Ctrl; n = 19) diet for three months. Following this, all mice were sacrificed and hearts were collected for weight measurement. Left ventricles were analyzed structurally by immunohistochemistry and molecularly by genome-wide expression profiling. E2 led to an increase in the heart weight (11%; P < 0.001) and the heart-to-body weight ratio (32%; P < 0.001) compared to Ctrl mice. Cardiomyocyte cross-sectional area revealed cardiomyocyte hypertrophy in E2 (n = 6) compared to Ctrl (n = 5) mice (32%; P = 0.004). Analysis of the left ventricular transcriptome identified 1059 probe sets (adjusted P ≤ 0.05) differentially expressed between E2 (n = 5) and Ctrl (n = 5). Hypergeometric testing for Gene Ontology showed most genes to be associated with cell cycle, regulation of growth, cell and tissue development. Pathway analysis revealed 140 pathways (adjusted P = 0.05) modulated between the two groups, such as the DNA replication and Wnt signaling pathways. Next, we tested the hypothesis that this hypertrophic effect of E2 is of the physiological type. To this extent, we identified that angiogenesis was increased with cardiac growth as determined by the microarray analysis and VEGF-A protein levels assessed by Western blotting. Furthermore, the embryonic gene program was not activated and no fibrosis was observed in the E2-treated group. In conclusion, our study is the first to demonstrate pro-hypertrophic actions of E2 in the healthy heart through the modulation of growth-related genes and pathways. Due to that we have characterized the hypertrophic effect of E2 as physiological, we expect this effect to be beneficial for the heart.

scholarly journals Heart size and mean muscle fibre cross-sectional area related to birth weight in pigs

2008 ◽  
Vol 16 (3) ◽  
pp. 259 ◽  
Author(s):  
M. RUUSUNEN ◽  
E. PUOLANNE ◽  
K. PARTANEN
Keyword(s):  
Birth Weight ◽  
Growth Performance ◽  
Muscle Mass ◽  
Carcass Composition ◽  
Cross Sectional Area ◽  
Heart Weight ◽  
Longissimus Dorsi ◽  
Muscle Fibres ◽  
Sectional Area ◽  
Cross Sectional

One of the aims in domestic pig breeding has been to increase the size of litters resulting in variation in birth weight of piglets. Pig breeding has also resulted in increased body muscle mass. Muscles with the same size can consist either of large number of thin muscle fibres or small number of thick muscle fibres. Larger body muscle content means that in living animal the heart must pump blood to larger muscle mass than earlier. Our interest in this study was to investigate the relationship between the pig’s birth weight and (i) growth performance and carcass composition, (ii) the size of organs, and (iii) the mean muscle fibre cross-sectional area at slaughter. The study consisted of twenty pigs slaughtered at the age of 165±2 days. The day after the slaughter, the carcass composition was determined by dissecting the chilled carcass into lean, fat, bones, and skin and organs were weighed. The average cross sectional area of muscle fibres was determined from three fast-twitch muscles longissimus dorsi, semimembranosus, gluteus superficialis, and two slow-twitch muscles infraspinatus and masseter. The birth weight of pigs ranged from 0.9 to 2.2 kg. We found no clear relationships between the birth weight and the pig’s growth performance from birth to slaughter. When the birth weight increased the heart weight at slaughter increased as well (P < 0.01). The heart weight was higher in those pigs with high carcass weight (P < 0.05) and with the high weight of total muscle mass in the carcass (P < 0.001). The cross sectional area of muscle fibres in M. longissimus dorsi (P < 0.05), M. semimembranosus (P < 0.10), and M. gluteus superficialis (P < 0.05) was larger in those pigs with low birth weight compared to those found in pigs with high birth weight.;

scholarly journals A transient antioxidant stress response accompanies the onset of disuse atrophy in human skeletal muscle

2009 ◽  
Vol 107 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Luciano Dalla Libera ◽  
Barbara Ravara ◽  
Valerio Gobbo ◽  
Elena Tarricone ◽  
Maurizio Vitadello ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Stress Response ◽  
Muscle Atrophy ◽  
Cross Sectional Area ◽  
Heme Oxygenase 1 ◽  
Sectional Area ◽  
Cross Sectional ◽  
Protein Levels ◽  
Antioxidant Stress

It is presently unknown whether oxidative stress increases in disused skeletal muscle in humans. Markers of oxidative stress were investigated in biopsies from the vastus lateralis muscle, collected from healthy subjects before [ time 0 (T0)], after 1 wk (T8), and after 5 wk (T35) of bed rest. An 18% decrease in fiber cross-sectional area was detected in T35 biopsies ( P < 0.05). Carbonylation of muscle proteins significantly increased about twofold at T35 ( P < 0.02) and correlated positively with the decrease in fiber cross-sectional area ( P = 0.04). Conversely, T8 biopsies showed a significant increase in protein levels of heme oxygenase-1 and glucose-regulated protein-75 (Grp75)/mitochondrial heat shock protein-70, two stress proteins involved in the antioxidant defense ( P < 0.05). Heme oxygenase-1 increase, which involved a larger proportion of slow fibers compared with T0, appeared blunted in T35 biopsies. Grp75 protein level increased threefold in T8 biopsies and localized especially in slow fibers ( P < 0.025), to decrease significantly in T35 biopsies ( P < 0.05). Percent change in Grp75 levels positively correlated with fiber cross-sectional area ( P = 0.01). Parallel investigations on rat soleus muscles, performed after 1–15 days of hindlimb suspension, showed that Grp75 protein levels significantly increased after 24 h of unloading ( P = 0.02), i.e., before statistically significant evidence of muscle atrophy, to decrease thereafter in relation to the degree of muscle atrophy ( P = 0.03). Therefore, in humans as in rodents, disuse muscle atrophy is characterized by increased protein carbonylation and by the blunting of the antioxidant stress response evoked by disuse.

Abstract 300: The Role of Rheb-mTORC1 Pathway in Cardiac Developmental Growth and Pathological Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Takahito Tamai ◽  
Tomokazu Murakawa ◽  
Osamu Yamaguchi ◽  
Shungo Hikoso ◽  
Issei Komuro ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cross Sectional Area ◽  
Heart Weight ◽  
Sectional Area ◽  
Cross Sectional ◽  
Pathological Hypertrophy ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway

Mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase and plays a key role in cellular growth. Multiprotein complexes called mTOR complex 1 (mTORC1) signaling is essential in cardiac hypertrophy. Many signaling pathways which can regulate mTORC1 activity have been previously reported, however, the regulation of mTORC1 is not fully elucidated. A small GTPase, Rheb (Ras homologue enriched in brain)-GTP activates mTORC1. In this study, to examine the contribution of Rheb in mTORC1 signaling in vivo hearts, we generated floxed Rheb mice to obtain cardiac-specific Rheb-deficient mice. First, to examine the role of Rheb-mTORC1 pathway in developmental cardiac hypertrophy, we generated Rheb-/- mice by crossing Rhebflox/flox mice with alpha MHC-Cre transgenic mice. Rheb-/- were born in Mendelian ratio. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb-/- were similar compared to those of control mice (Rheb+/+) 5 days after birth. However, all of them died between 8 and 10 days after birth due to cardiac dysfunction and heart failure. Rheb-/- exhibited cardiac dilatation and reduced contractility 8 days after birth. The heart weight to body weight ratio and the cross-sectional area of cardiomyocytes were significantly lower in Rheb-/- 8 days after birth. Next, to examine the role of Rheb-mTORC1 pathway in pathological hypertrophy, we generated conditional Rheb-/- mice by crossing Rhebflox/flox mice with Mer-Cre-Mer transgenic mice. Cardiac pressure overload was induced by means of transverse aortic constriction (TAC), and mice were sacrificed one week after TAC. The heart weight to tibia length ratio and the cross-sectional area of cardiomyocytes were significantly increased in both TAC-operated control and conditional Rheb-/- group compared to that of corresponding sham-operated group. Taken together, Rheb is not essential in pathological hypertrophy, but is essentilal in cardiac developmental hypertrophy in the post-neonatal period.

Abstract 73: Aberrant Activation of γ2-AMPK Increases Cardiac Growth Through Cellular Hypertrophy and Hyperplasia

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Maengjo Kim ◽  
Roger Hunter ◽  
Kei Sakamoto ◽  
Stephen Kolwicz ◽  
Lorena Menendez ◽  
...  
Keyword(s):  
Cardiac Myocyte ◽  
Glycogen Synthase ◽  
Fold Increase ◽  
Glycogen Storage ◽  
Nuclear Antigen ◽  
Heart Weight ◽  
Target Point ◽  
Cross Sectional ◽  
Cardiac Growth ◽  
Cellular Hypertrophy

AMP-activated protein kinase (AMPK) is an energy sensor and a key regulator of cell metabolism, hence a promising drug target. Point mutations in the regulatory γ2-subunit (encoded by PRKAG2 gene) have been shown to cause a unique form of cardiomyopathy in humans characterized by cardiac growth, arrhythmias and glycogen storage. In previous studies, we demonstrated that the mutation of prkag2 (N488I) caused aberrant activation of AMPK leading to glycogen storage. However, elimination of glycogen storage by inhibiting glycogen synthase activity failed to normalize heart weight (HW) of the mutant mice. Here, we aimed to determine whether cardiac growth in PRKAG2 ardiomyopathy was dueto cellular hypertrophy or hyperplasia. We used transgenic mice expressing a mutant PRKAG2 (N488I) in the heart (TGγ2 N488I ) that faithfully recapitulated PRKAG2 cardiomyopathy. We determined HW and cardiac myocyte size in adult (2 months) and postnatal (2 weeks) hearts in WT and TGγ2 N488I . At 2 months, TGγ2 N488I hearts show a 2.4-fold increase in HW/BW (body weight) (10.3 ± 1.44 vs. 4.3± 0.17 mg/g) as well as cross-sectional cell surface area compared WT hearts (325 ± 13 vs. 155 ± 5.4 μm 2 ,p<0.01), suggesting cellular hypertrophy in adult TGγ2 N488I heart. Furthermore, we observed increased mTOR activity evidenced by enhanced phosphorylation of mTOR (Ser2448) as well as its downstream targets S6 and 4E-BP. The HW of TGγ2 N488I was partially inhibited by treatment with rapamycin, an inhibitor of mTOR. Interestingly, the length and width of isolated cardiomyocytes from 2 weeks old mice were not different between the WT and TGγ2 N488I heart in spite of a 50% increase of HW of TGγ2 N488I mice. We observed a 2- fold increase in the expression of a proliferation marker, proliferating cell nuclear antigen (PCNA) during postnatal cardiac growth. Expression of Cyclin genes including cyclin D1, D2 and E1 was greatly increased in TGγ2 N488I hearts (2.4 - 4 fold, p<0.01 vs. WT). Taken together, these data indicate that aberrant γ2-AMPK activation stimulates cardiac growth through increased cell number during postnatal growth period and increased cell size at adulthood. These results suggest a novel role of γ2-AMPK in the growth of cardiac myocytes.

Pelvic Canal Narrowing Caused by Triple Pelvic Osteotomy in the Dog

1994 ◽  
Vol 07 (03) ◽  
pp. 110-113 ◽  
Author(s):  
D. L. Holmberg ◽  
M. B. Hurtig ◽  
H. R. Sukhiani
Keyword(s):  
Postoperative Complications ◽  
Pelvic Osteotomy ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Cross Sectional ◽  
Canal Width ◽  
Operative Complications ◽  
Post Operative Complications

SummaryDuring a triple pelvic osteotomy, rotation of the free acetabular segment causes the pubic remnant on the acetabulum to rotate into the pelvic canal. The resulting narrowing may cause complications by impingement on the organs within the pelvic canal. Triple pelvic osteotomies were performed on ten cadaver pelves with pubic remnants equal to 0, 25, and 50% of the hemi-pubic length and angles of acetabular rotation of 20, 30, and 40 degrees. All combinations of pubic remnant lengths and angles of acetabular rotation caused a significant reduction in pelvic canal-width and cross-sectional area, when compared to the inact pelvis. Zero, 25, and 50% pubic remnants result in 15, 35, and 50% reductions in pelvic canal width respectively. Overrotation of the acetabulum should be avoided and the pubic remnant on the acetabular segment should be minimized to reduce postoperative complications due to pelvic canal narrowing.When performing triple pelvic osteotomies, the length of the pubic remnant on the acetabular segment and the angle of acetabular rotation both significantly narrow the pelvic canal. To reduce post-operative complications, due to narrowing of the pelvic canal, overrotation of the acetabulum should be avoided and the length of the pubic remnant should be minimized.

DETERMINATION OF THE FUNCTION OF THE ROD’S CROSS-SECTIONAL AREA USING VIBRATION EIGENFREQUENCIES

2020 ◽  
Vol 0 (4) ◽  
pp. 19-24
Author(s):  
I.M. UTYASHEV ◽  
◽  
A.A. AITBAEVA ◽  
A.A. YULMUKHAMETOV ◽  
◽  
...  
Keyword(s):  
Cross Sectional Area ◽  
Variable Cross ◽  
Sectional Area ◽  
Longitudinal Vibrations ◽  
Cross Sectional ◽  
Method Error ◽  
Various Boundary Conditions ◽  
Elastic Fixation ◽  
Crosssectional Area

The paper presents solutions to the direct and inverse problems on longitudinal vibrations of a rod with a variable cross-sectional area. The law of variation of the cross-sectional area is modeled as an exponential function of a polynomial of degree n . The method for reconstructing this function is based on representing the fundamental system of solutions of the direct problem in the form of a Maclaurin series in the variables x and λ. Examples of solutions for various section functions and various boundary conditions are given. It is shown that to recover n unknown coefficients of a polynomial, n eigenvalues are required, and the solution is dual. An unambiguous solution was obtained only for the case of elastic fixation at one of the rod’s ends. The numerical estimation of the method error was made using input data noise. It is shown that the error in finding the variable crosssectional area is less than 1% with the error in the eigenvalues of longitudinal vibrations not exceeding 0.0001.

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