Date of Award
Spring 2018
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
First Advisor
Fitts, Robert H.
Second Advisor
Buchanan, James T.
Third Advisor
Mynlieff, Michelle
Abstract
Heart disease is one of the leading causes of morbidity and mortality in the western world, and programs of exercise-training have been shown to ameliorate cardiovascular risk factors and protect against heart diseases. The cellular/molecular mechanisms of regular exercise induced adaptations in the heart remains incomplete. To address this, female and male Sprague-Dawley rats were randomly assigned to exercise trained (TRN) or sedentary (SED) groups. After 6-8 weeks training, ventricular myocytes were isolated and studied.Exercise-training prolonged the action potential duration (APD) in myocytes isolated from apex and base regions at low stimulation rate (1Hz), while shortening the APD at high stimulation (10Hz). The exercise-induced effect on the Ca2+ transient duration reflected the changes observed in APD. Wheel running shifted the β-adrenergic receptor (β-AR) agonist dose-response curve rightward compared to SED by reducing β1-AR responsiveness. Wheel-running significantly increased myocyte shortening velocity and rate of intracellular Ca2+ rise with 1, 2 and 5 Hz stimulation, while the extent of shortening increased only at 5 Hz. At 1 & 2 Hz, β-AR agonist accelerated sarcomere shortening & relaxation velocity and rate of intracellular Ca2+ decline in TRN and SED, but increased sarcomere shortening only in TRN. The β-AR agonist effect was dose dependent in TRN but not SED.Pharmacological studies of myocytes showed higher ATP sensitive potassium channel (KATP) function in ventricular repolarization and larger KATP currents in TRN compared to SED. Exercise-training elevated the KATP channel pore forming protein subunit Kir6.2 content in apex and regulatory protein subunit SUR2A content in base regions of male and female rats. Rapidly activating delayed rectifier potassium channel (Ikr) contributes relatively little to ventricular repolarization compared to slowly activating delayed rectifier potassium channel IKs in both male and female rats, and higher IKs current was observed in apex compared to base region. Exercise-training decreased IKs current as well as the content of IKs channel protein subunits KCNQ1 and KCNE1. β-agonist significantly elevated IKs current density and exercise-training decreased IKs responsiveness to β-AR stimulation.The down-regulation of IKs provides a molecular basis for prolonged APD and Ca2+ transient observed in TRN rats with 1Hz stimulation, which contributes to enhanced cardiac contractility and efficiency at rest. The up-regulation of KATP channel in TRN rats largely explains the exercise-induced APD shortening at 10Hz, which helps reduce the energy consumption and maintain diastolic interval adequate for myocardial relaxation at high heart rates. A novel finding was that exercise-training elevated kinetics of sarcomere shortening/relaxation and its response to β-AR stimulation.