Abstract 395: Voluntary Exercise Enhances Cardiac Growth in Response to Chronic β-Adrenergic Receptor Stimulation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Stephen W Luckey ◽  
Nathan McLaughlin ◽  
Sherilynn Soo
Keyword(s):  
Exercise Capacity ◽  
Adrenergic Receptor ◽  
Wheel Running ◽  
Voluntary Exercise ◽  
Published Data ◽  
Receptor Stimulation ◽  
Cardiac Growth ◽  
Heart Size ◽  
Underlying Mechanisms

Exercise training protects the heart against the adverse effects of cardiovascular disease. Recent studies have identified a number of cardiac adaptations including the activation of hypertrophic signaling pathways unique to exercise. However, the underlying mechanisms by which exercise confers cardioprotection are not entirely understood. This study aims to fill this gap by examining the role of voluntary exercise in the context of chronic β-adrenergic receptor stimulation. To do this, we developed a novel experimental model in which nine-week-old female and male CB6F1 hybrid mice were subjected to 5 weeks of voluntary wheel running (EX) or housed under sedentary conditions (SED). For the final two weeks, mice were administered either vehicle (VEH) or isoproterenol (ISO, 30mg/kg/day) via an osmotic pump. As expected, we found that ISO significantly increased heart size in sedentary females and males (SED+ISO) compared to sedentary mice receiving VEH (SED+VEH). Consistent with previously published data, exercise capacity was also greater in females compared to males with regards to running duration and distance regardless of the experimental group. While exercise capacity was not affected by the administration of VEH, mice receiving ISO (EX+ISO) exercised significantly less. Cardiac growth in EX+VEH mice was significantly increased in both females and males compared to their respective SED+VEH counterparts. Importantly, EX+ISO females and males have significantly larger hearts than their respective SED+ISO cohorts. Moreover, EX+ISO mice also exhibited greater increases in cardiac size as compared to their respective EX+VEH counterparts. Thus, we conclude that there appears to be an additive effect of voluntary exercise and ISO administration in both females and males in terms of cardiac growth. These preliminary data are in contrast to previously published data which found that controlled exercise programs reduced cardiac hypertrophy under conditions of chronic β-adrenergic receptor stimulation. We are currently investigating the processes that lead to the larger heart sizes in the EX+ISO mice and aim to better understand the underlying mechanisms of exercise-mediated cardioprotection.

Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Michael Coronado ◽  
Giovanni Fajardo ◽  
Kim Nguyen ◽  
Mingming Zhao ◽  
Kristina Bezold Kooiker ◽  
...  
Keyword(s):  
Cell Death ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Adrenergic Receptor ◽  
Mitochondrial Fission ◽  
Physiological Adaptation ◽  
Mitochondrial Fragmentation ◽  
Energetic Demand ◽  
Adaptation To Exercise

Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.

scholarly journals β-Adrenergic receptor stimulation inhibits proarrhythmic alternans in postinfarction border zone cardiomyocytes: a computational analysis

2017 ◽  
Vol 313 (2) ◽  
pp. H338-H353 ◽  
Author(s):  
Jakub Tomek ◽  
Blanca Rodriguez ◽  
Gil Bub ◽  
Jordi Heijman
Keyword(s):  
Adrenergic Receptor ◽  
Border Zone ◽  
Adrenergic Stimulation ◽  
Cell Coupling ◽  
Postmyocardial Infarction ◽  
Model Cell ◽  
Cycle Lengths ◽  
Underlying Mechanisms ◽  
First Time

The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca2+ and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation. The BZ model developed Ca2+ transient alternans at slower pacing cycle lengths than the control model, suggesting that the BZ may promote spatially heterogeneous alternans formation in an infarcted heart. β-AR stimulation abolished alternans. By evaluating all combinations of downstream β-AR stimulation targets, we identified both direct (via ryanodine receptor channels) and indirect [via sarcoplasmic reticulum (SR) Ca2+ load] modulation of SR Ca2+ release as critical determinants of Ca2+ transient alternans. These findings were confirmed in a human ventricular cardiomyocyte model. Cell-to-cell coupling indirectly modulated the likelihood of alternans by affecting the action potential upstroke, reducing the trigger for SR Ca2+ release in one-dimensional strand simulations. However, β-AR stimulation inhibited alternans in both single and multicellular simulations. Taken together, these data highlight a potential antiarrhythmic role of sympathetic hyperinnervation in the BZ by reducing the likelihood of alternans and provide new insights into the underlying mechanisms controlling Ca2+ transient and repolarization alternans. NEW & NOTEWORTHY We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of β-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that β-adrenergic stimulation inhibits alternans and provide novel insights into underlying mechanisms, adding to a recent controversy about pro-/antiarrhythmic effects of postmyocardial infarction hyperinnervation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/%CE%B2-ar-stimulation-and-alternans-in-border-zone-cardiomyocytes/ .

ALTERATIONS OF FIBRINOLYSIS AND BLOOD COAGULATION INDUCED BY EXERCISE, AND THE ROLE OF BETA-ADRENERGIC-RECEPTOR STIMULATION

The Lancet ◽  
1968 ◽  
Vol 292 (7581) ◽  
pp. 1264-1266 ◽  
Author(s):  
RichardJ. Cohen ◽  
StephenE. Epstein ◽  
LawrenceS. Cohen ◽  
LewisH. Dennis
Keyword(s):  
Blood Coagulation ◽  
Adrenergic Receptor ◽  
Beta Adrenergic Receptor ◽  
Receptor Stimulation ◽  
Beta Adrenergic

scholarly journals Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiotoxicity

2019 ◽  
Vol 18 ◽  
pp. 153473541984399 ◽  
Author(s):  
Stephanie E. Hall ◽  
Ashley J. Smuder ◽  
Reid Hayward
Keyword(s):  
Calorie Restriction ◽  
Wheel Running ◽  
Systolic Pressure ◽  
Protective Role ◽  
Left Ventricular ◽  
Voluntary Exercise ◽  
Pressure Development ◽  
Developed Pressure ◽  
Fractional Shortening

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity. Methods: Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation. Results: Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dtmax) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dtmax, and dP/dtmin were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group. Conclusion: This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.

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