Abstract 168 Cardiology: Mouse Models and Basic Mechanisms of Cardiac Disease Platform, Tuesday, 5/4

Chronic exercise conditioning is mediated by a multitude of cardiovascular and metabolic alterations. Studies using β1-adrenergic receptor knockout (β1-AR -/-) mice have shown that intact β-AR signaling is critical for regulation of cardiac inotropy and chronotropy, however, is not required for maintenance of normal acute exercise capacity. The purpose of this study was to test the hypothesis that mice can be conditioned using a treadmill exercise training regimen and to determine the role of β1-ARs in the conditioning response. Wild-type (WT) mice and β1-AR-/- mice were trained using a 12 wk running program with gradually increasing workload (COND). Age matched sedentary controls were cage confined for 12 wks (SED). Baseline data (pre) were recorded for body wt and VO2. Graded treadmill exercise was then initiated at 3 m/min, 0° inclination, and increasing by 2.5 m/min and 2° inclination every 3 min until exhaustion. Maximal exercise capacity and VO2 were recorded. After the 12-wk study period, these measurements were repeated (post) along with measurements of heart rate (HR), blood pressure (BP) and lactate at submaximal workload. Hearts were excised and weighed. In all mice, resting VO2 decreased with age, but to the same degree in SED and COND mice. WT mice demonstrated a significant conditioning response as evidenced by increased distance run (COND 398 m pre vs. 554 m post; SED 392 m pre vs. 323 m post), decreased VO2 at equivalent workloads, and decreased lactate at submaximal exercise (44±9 vs 80±21). However HR response and heart wt/body wt ratio were not significantly different. β1-AR -/- mice showed similar conditioning responses, with the exception of an attenuated decrease in VO2 at equivalent workloads. β1-AR-/- mice had lower HR at all workloads compared with WT mice, however HR response was not affected by conditioning. COND β1-AR -/- mice had submaximal exercise lactate levels similar to COND WT mice. Finally, COND β1-AR-/- mice did show an increased heart wt/body wt ratio (7.2 × 10-3 vs. 4.8 × 10-3). We conclude that mice can be conditioned by chronic dynamic exercise, further validating the use of gene targeted murine models for studies of human cardiovascular diseases. We also conclude that signal transduction mediated through the β1-AR does not play a major role in cardiovascular conditioning but does result in subtle alterations in the metabolic response to conditioning.