Abstract 314: Inactivation-Resistant GSK3αβ Dual Isoform Expression Attenuates Isoproterenol-Induced Myocardial Hypertrophy and Preserves Cardiac Function

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ian G Webb ◽  
Yasuhiro Nishino ◽  
James E Clark ◽  
Colin E Murdoch ◽  
Ajay M Shah ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Glycogen Synthase ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Heart Weight ◽  
Age Related ◽  
Ventricular Wall Thickness ◽  
Isoform Expression ◽  
Gsk 3Β ◽  
Opposing Effects

Glycogen synthase kinase-3 (GSK-3) is implicated as an important signalling mediator in normal developmental myocardial growth and adverse hypertrophic remodelling. Upstream phosphorylation of isoform specific N-terminal serine residues - ser21(GSK-3α) and ser9(GSK-3β), respectively - inhibits kinase activity. Opposing effects of the two isoforms have recently been described in response to hypertrophic stimuli, but little is known of the overall effect of dual-isoform manipulation. We set out to characterise baseline and isoproterenol (ISO) stimulated phenotypes of mice with inactivation-resistant GSK-3αβ knockin (KI) alleles, in which ser21/9 are converted to non-phosphorylatable alanine. Between 5–15 weeks there was a non-significant trend towards higher heart weight (HW): body weight (BW) ratios in KI mice versus wild type (WT) mice. Mean left ventricular wall thickness (LVWT) at the level of the papillary muscle was comparable between genotypes (1.3±0.2mm vs 1.6±0.2mm, ns, n=8). 8–10 week old weight-matched mice received 2 weeks subcutaneous ISO (30mg/kg/d) or control saline (Con) infusions. WT hearts hypertrophied with ISO (LVWT 1.9±0.1mm vs 1.3±0.2mm Con, n=8; HW:BW ratio 6.7±0.6 vs 5.4±0.4 Con, n=10, both p< 0.05), but KI mice did not (1.4±0.1mm vs 1.6±0.2mm KI Con; HW:BW 6.2±1.0 vs 6.1±0.6 KI Con, respectively, both ns). Hypertrophy in the WT hearts was associated with reduced LV ejection fraction (41±9% vs 63±5% Con, n=6, p< 0.05) and greater interstitial fibrosis (2.1±0.5% vs 0.8±0.6%, n=6, p< 0.05). These were both attenuated in the KI mice subjected to ISO (70±13% vs 64±11% Con, and 1.3±0.7% vs 0.8±0.3% Con, respectively, both ns). GSK-3 inhibition with daily intraperitoneal 6-bromoindirubin-3′-oxime restored hypertrophic sensitivity to ISO in the KI mice (LVWT 1.8±0.2mm; HW:BW 7.3±0.5, p< 0.05 for both groups vs KI + ISO alone) but had no effect in the absence of hypertrophic stimulus (1.4±0.2mm and 5.4±0.7, respectively, for KI + Con + Bio, ns vs KI + Con alone). In conclusion, inactivation-resistant GSK-3αβ dual isoform expression does not affect age-related (eutrophic) myocardial growth in the mouse. However, it protects against pathological growth, maintaining cardiac function and attenuating interstitial fibrosis.

Abstract 16161: GSK-3β Activates Autophagy and Protects Against Cardiac Aging Through Ulk1

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Takanobu Yamamoto ◽  
Yoshiyuki Ikeda ◽  
Bonaventure Magrys ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Left Ventricular ◽  
Protective Mechanism ◽  
Cross Sectional ◽  
Cardiac Aging ◽  
Beneficial Effects ◽  
Stiffness Constant ◽  
Age Related ◽  
Gsk 3Β

Accumulating lines of evidence suggest that glycogen synthase kinase-3β (GSK-3β) is involved in aging. However, the effects of GSK-3β on cardiac aging and the underlying mechanisms remain to be elucidated. Autophagy, a protective mechanism in aging, decreases with age. We hypothesized that GSK-3β attenuates cardiac aging via Ulk1, a regulator of autophagy, and studied constitutively active GSK-3βS9A knock-in mice (βKI), GSK-3βS9A/Ulk1+/- bigenic mice (Bigenic), and GSK-3β+/- mice (βKO) up to 24 months (M) of age. Left ventricular (LV) weight/body weight (LVW/BW, mg/g) was not significantly different among wild-type mice (WT), βKI and βKO at 6M. It was lower in βKI (2.4±0.1, p<0.005) and higher in βKO (4.8±0.8, p<0.05) than in WT (3.8±0.2) at 24M. Cardiomyocyte cross-sectional area (CSA, μm2) was smaller in βKI (360±9, p<0.001) but bigger in βKO (540±11, p<0.01) than in WT (502±5) at 24M. The LVW/BW was greater (3.5±0.2, p<0.001) and the CSA was bigger (527±4, p<0.001) in Bigenic than in βKI at 24M. These data demonstrate that GSK-3β inhibits age-dependent cardiac hypertrophy via Ulk1. Cardiac fibrosis (%) was more in βKO (5.4±0.1, p<0.001) and less in βKI (2.4±0.1, p<0.001) than in WT (4.0±0.3) at 24M. There was much more fibrosis in Bigenic (5.5±0.6, p<0.001) than in βKI at 24M. These data show that GSK-3β reduces age-related cardiac fibrosis via Ulk1. LV end-systolic elastance (Ees, mmHg/μl) and chamber stiffness constant (CSC, μl-1) were not significantly different among WT, βKI, and βKO at 6M. At 24M, the Ees was lower in βKO (4±1, p<0.05) and higher in βKI (12±3, p<0.05) than in WT (7±0), and the CSC was higher in βKO (0.19±0.01, p<0.001) and lower in βKI (0.06±0.01, p<0.001) than in WT (0.14±0.01). The beneficial effects of GSK-3β on cardiac function were abolished in the Bigenic, indicating that GSK-3β prevents age-specific cardiac dysfunction via Ulk1. The level of p62, a protein degraded by autophagy, was lower in βKI and higher in βKO than in WT. The numbers of autophagosomes and autolysosomes were significantly greater in βKI/tfLC3 (tandem fluorescent mRFP-GFP-LC3) mice than in tfLC3 or βKI/tfLC3/Ulk1+/- mice. These data suggest that GSK-3β activates autophagy via Ulk1. In conclusion, GSK-3β attenuates cardiac aging by activating Ulk1-dependent autophagy.

Abstract 12999: Senescence Marker Protein 30 Protect the Cardiac Injury From After Ischemia Reperfusion

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shinpei Kadowaki ◽  
Tetsuro Shishido ◽  
Taro Narumi ◽  
Yuki Honda ◽  
Satoshi Nishiyama ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Marker Protein ◽  
Age Related ◽  
Ribosomal S6 Kinase ◽  
Gsk 3Β

Background: Successful myocardial reperfusion is effective therapy for improving the clinical outcome after acute myocardial infarction, nevertheless reperfusion injury can paradoxically induces cardiomyocyte dysfunction. Moreover, recovery of cardiac function is impaired with aging. Glycogen synthase kinase-3β (GSK-3β) and p70 ribosomal S6 kinase (p70S6K) are cardioprotective against I/R via mitochondrial dysfunction. Senescence marker protein-30 (SMP30), which regulates mitochondrial quality and decreases with aging, is an organ-protective protein; however the protective role of SMP30 against ischemia/reperfusion (I/R) has not been clearly determined yet. Methods and Result: Firstly, we confirmed that SMP30 expressions in the heart were progressively decreased with aging. In vitro study, we also found that reactive oxygen species decreased expression levels of SMP30 in neonatal cardiomyocyte. Depletion of SMP30 increased apoptotic cardiomyocyte death after hydrogen peroxide stimulation. To evaluate the cardioprotective role of SMP30, we induced 30 min ischemia and 24-hr reperfusion (I/R) in WT and SMP30 KO mice. Phosphorylation levels of p70S6K and GSK-3β in the heart were increased after IR in WT mice; however those phosphorylation were attenuated in SMP30 KO mice. SMP30 KO mice after I/R had significantly larger numbers of apoptotic cardiomyocyte than WT mice ( 10.5± 5.7% vs. 4.0± 1.7%, p < 0.05), that correlated with a significant expansion in infarct size and a significant reduction of left ventricular fractional shortening (37.3± 4.3% vs 43.4± 5.1%, p < 0.01). Conclusions: These results suggest that reduction of SMP30 levels with aging is associated with age-related dysfunction after ischemia-reperfusion through disability to phosphorylate p70S6K and GSK-3β. Thus, SMP30 might be a novel therapeutic target for the treatment of acute myocardial infarction in elderly patient.

scholarly journals Cardiac MRI in common marmosets revealing age-dependency of cardiac function

2020 ◽  
Author(s):  
Amir Moussavi ◽  
Matthias Mietsch ◽  
Charis Drummer ◽  
Rüdiger Behr ◽  
Judith Mylius ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Cardiac Function ◽  
Cardiac Mri ◽  
Left Ventricular ◽  
Heart Weight ◽  
Imaging Protocol ◽  
Common Marmosets ◽  
Age Related ◽  
Significant Difference ◽  
The Right

The aim of this study was to establish a feasible and robust magnetic resonance imaging protocol for the quantitative assessment of cardiac function in marmosets and to present normal values of cardiac function across different ages from young adult, middle-aged, to very old clinically healthy animals.Cardiac MRI of 33 anesthetized marmosets at the age of 2-15 years was performed at 9.4 T using IntraGate-FLASH that operates without any ECG-triggering and breath holding. Normalized to post-mortem heart weight, the left ventricular end-diastolic volume (LV-EDV) was significantly reduced in older marmosets. The LV end-systolic volume (LV-ESV) and the LV stroke volume (LV-SV) showed a similar trend while the LV ejection fraction (LV-EF) and wall thickening remained unchanged. Similar observations were made for the right ventricle. Moreover, the total ventricular myocardial volume was lower in older monkeys while no significant difference in heart weight was found.In conclusion, IntraGate-FLASH allowed for quantification of left ventricular cardiac function but seems to underestimate the volumes of the right ventricle. Although less strong and without significant sex differences, the observed age related changes were similar to previously reported findings in humans supporting marmosets as a model system for age related cardiovascular human diseases.

Abstract 3426: Myostatin Deletion Preserves Cardiac Function in Senescent Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Morissette ◽  
Janelle C Stricker ◽  
Anthony Rosenzweig
Keyword(s):  
Cardiac Function ◽  
Rhode Island ◽  
Cardiac Fibrosis ◽  
Physiological Role ◽  
Heart Association ◽  
Negative Regulator ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels ◽  
Age Related

Myostatin (MSTN) is a well-known negative regulator of skeletal muscle mass, and MSTN inhibition is being considered as therapy for multiple conditions associated with muscle wasting, including sarcopenia of aging. We have previously shown that MSTN inhibits phenylephrine-induced cardiomyocyte hypertrophy, however whether MSTN has a physiological role in regulating cardiac hypertrophy or function at baseline or with aging remains unclear. To determine if MSTN is dynamically regulated with aging, we performed QRT-PCR on hearts from male wild-type (WT) senescent mice (24 months old (mos)) and rats (32 mos). MSTN mRNA levels were increased in old versus young (4 mos) hearts (2.5- and 4-fold respectively, p<0.05). To study the functional significance of MSTN in aging, we maintained germline MSTN-knockout mice (MSTN −/− ) and their WT littermates for 24 –27 months. We found no difference in heart weight of aged male MSTN −/− compared to WT mice (162.5±17.0 (n=4) vs 153.2±4.2 (n=4) mg, p=0.51), which would argue against an inhibitory role for MSTN in age-related increases in cardiac mass. We also performed echocardiography on unanesthetized senescent MSTN −/− and WT mice. MSTN −/− mice had better fractional shortening (58.1±2.0 (n=7) vs 49.4±1.2 (n=8) %, p=0.002) and smaller LV end-diastolic diameter (3.41±0.19 vs 2.71±0.14 mm, p=0.012) compared to WT. The decreased cardiac function seen in aged WT mice was associated with increased cardiac fibrosis on Masson-Trichrome stained sections. Western blot analysis also demonstrated a 3.3-fold increase in phospholamban phosphorylation in MSTN −/− hearts (p<0.05), compared to WT, while no differences in SERCA2a or calsequestrin protein levels were seen. We conclude that MSTN increases in the heart with aging, and that genetic deletion of MSTN results in improved cardiac function without a difference in heart mass in senescent mice. Decreased cardiac fibrosis and increased inhibition (phosphorylation) of phospholamban likely contribute to the better cardiac function seen in senescent MSTN −/− mice. These results suggest that inhibiting MSTN for sarcopenia in the elderly may also benefit cardiac function and could represent a novel therapeutic approach for ameliorating cardiac dysfunction and/or fibrosis. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Abstract 122: Cardiac mTOR Preserves Cardiac Function Following Ex Vivo Ischemia-Reperfusion in Diet-Induced Obese Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toshinori Aoyagi ◽  
Takashi Matsui
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Cardiac Function ◽  
Glucose Intolerance ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Diabetic Patients ◽  
Significant Difference

The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mammalian target of rapamycin (mTOR), a key downstream molecule of insulin-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, plays an important role in cardioprotection. However, the role of cardiac mTOR in ischemic injury in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpressing cardiac mTOR on cardiac function following ischemia/reperfusion (I/R) in mice with high-fat diet (HFD)-induced obesity. In this study, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) as reported previously. mTOR-Tg and WT mice at 6 weeks old were fed HFD (60% fat by calories) ad libitum for 14 weeks. Control mTOR-Tg and WT mice were fed a normal chow diet (NCD). At 14 weeks after HFD, glucose and insulin tolerance tests demonstrated that HFD generated glucose intolerance and insulin resistance in both mTOR-Tg (n=20) and WT (n=24) mice. Body weight (BW) and heart weight (HW) were significantly higher in HFD mice than SCD mice (p<0.001 for BW in both strains; p<0.001 and p<0.01 for HW/tibia length, WT and mTOR-Tg, respectively) but there was no difference in BW or HW between HFD-mTOR-Tg and HFD-WT mice. Hearts from all four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. Baseline left ventricular developed pressure (LVDP) was higher in HFD mice than NCD mice in both strains [185.8 ± 10.7 vs. 143.6 ± 5.0 mmHg, HFD-WT (n=11) vs. NCD-WT (n=10) mice, p<0.01; 178.6 ± 10.1 vs. 135.0 ± 6.3, HFD-mTOR-Tg (n=8) vs. NCD-mTOR-Tg (n=11) mice, p<0.01]. Functional recovery after I/R was significantly lower in HFD-WT mice than NCD-WT mice (percent recovery of LVDP, 15.3 ± 5.4 vs. 44.6 ± 6.3 %, HFD-WT vs. NCD-WT mice, p<0.01). Intriguingly, there was no significant difference in LVDP recovery between HFD-mTOR-Tg and NCD-mTOR-Tg mice (36.5±10.8 vs. 58.8±6.0 %, HFD-mTOR-Tg vs. NCD-mTOR-Tg mice, n.s.). These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

2011 ◽  
Vol 441 (1) ◽  
pp. 199-207 ◽  
Author(s):  
Ruomin Di ◽  
Xiangqi Wu ◽  
Zai Chang ◽  
Xia Zhao ◽  
Qiuting Feng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
S6 Kinase ◽  
Beneficial Effects ◽  
Therapeutic Value ◽  
Specific Deletion

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic rats

1999 ◽  
Vol 86 (3) ◽  
pp. 812-818 ◽  
Author(s):  
Kiminori Kato ◽  
Donald C. Chapman ◽  
Heinz Rupp ◽  
Anton Lukas ◽  
Naranjan S. Dhalla
Keyword(s):  
Heart Rate ◽  
Cardiac Function ◽  
Atpase Activity ◽  
Binding Sites ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Carnitine Palmitoyltransferase ◽  
Heart Weight ◽  
High Affinity

To examine the role of changes in myocardial metabolism in cardiac dysfunction in diabetes mellitus, rats were injected with streptozotocin (65 mg/kg body wt) to induce diabetes and were treated 2 wk later with the carnitine palmitoyltransferase inhibitor (carnitine palmitoyltransferase I) etomoxir (8 mg/kg body wt) for 4 wk. Untreated diabetic rats exhibited a reduction in heart rate, left ventricular systolic pressure, and positive and negative rate of pressure development and an increase in end-diastolic pressure. The sarcolemmal Na+-K+-ATPase activity was depressed and was associated with a decrease in maximal density of binding sites (Bmax) value for high-affinity sites for [3H]ouabain, whereas Bmax for low-affinity sites was unaffected. Treatment of diabetic animals with etomoxir partially reversed the depressed cardiac function with the exception of heart rate. The high serum triglyceride and free fatty acid levels were reduced, whereas the levels of glucose, insulin, and 3,3′,-5-triiodo-l-thyronine were not affected by etomoxir in diabetic animals. The activity of Na+-K+-ATPase expressed per gram heart weight, but not per milligram sarcolemmal protein, was increased by etomoxir in diabetic animals. Furthermore, Bmax (per g heart wt) for both low-affinity and high-affinity binding sites in control and diabetic animals was increased by etomoxir treatment. Etomoxir treatment also increased the depressed left ventricular weight of diabetic rats and appeared to increase the density of the sarcolemma and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a shift in myocardial substrate utilization may represent an important signal for improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic rat hearts with impaired glucose utilization.

Chronic β-agonist administration affects cardiac function of adult but not old rats, independent of β-adrenoceptor density

2005 ◽  
Vol 289 (1) ◽  
pp. H344-H349 ◽  
Author(s):  
Paul Gregorevic ◽  
James G. Ryall ◽  
David R. Plant ◽  
Martin N. Sillence ◽  
Gordon S. Lynch
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Heart Function ◽  
Relative Increase ◽  
Left Ventricular ◽  
Aged Rats ◽  
Adult Rats ◽  
Age Related ◽  
Heart Mass

Although β-adrenoceptor agonists have clinical merit for attenuating the age-related loss of skeletal muscle mass and strength (sarcopenia), potential cardiac-related side effects may limit their clinical application. The aim of this study was to determine whether chronic β-agonist administration impairs cardiac function in adult or aged rats. Adult (16 mo) and aged (28 mo) Fischer 344 rats were treated with fenoterol (1.4 mg·kg−1·day−1 ip) or vehicle for 4 wk. Heart function was assessed in vitro before analyses of cardiac structure and β-adrenoceptor density. Heart mass increased 17% and 25% in fenoterol-treated adult and aged rats, respectively. The increased heart mass in aged, but not adult, rats was associated with a relative increase in collagen content. Cardiac hypertrophy in adult rats was associated with an increase in left ventricular developed pressure, a marked reduction in cardiac output, and a reduction in coronary flow per unit heart mass. In contrast, negligible differences in ventricular function were observed in fenoterol-treated aged rats. The differential effect on contractile function was not associated with age-related differences in β-adrenoceptor density but, rather, an age-related increase in downregulation after treatment. Our results show that chronic β-agonist treatment impairs cardiac function to a greater extent in adult than in aged rats. These results provide important information regarding the potential effects of chronic β-agonist use on cardiac function and the future development of safe and effective treatments for sarcopenia.

Sign in / Sign up

Export Citation Format

Share Document