Abstract 15625: Insulin Receptor Substrates (IRS) Regulate the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
To test the hypothesis that insulin receptor substrate (IRS) isoforms mediate the cardiac growth and metabolic adaptations that follow exercise training, mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1KO) or IRS2 (CIRS2KO) were subjected to swim training (Ex). At 12 weeks of age, heart weight-to-tibia length ratios (HW/TL) were reduced by 12.5% (p<0.05) in CIRS1KO versus WT under sedentary conditions (Sed). In contrast, HW/TL was increased in CIRS2KO by 10% (p<0.05) at the same age. Following 5 wk exercise swim training, WT mice increased HW/TL by 11.7% (p<0.05). However, CIRS1KO and CIRS2KO showed no increase in HW/TL (5.50 vs. 5.57 mg/mm and 6.97 vs. 6.98 mg/mm respectively). Phosphorylation of Akt (Thr308) increased in WT hearts following Ex (2.28fold, p<0.05) while no increase was observed in CIRS1KO and CIRS2KO hearts. ADP-stimulated mitochondrial oxygen consumption (V-ADP) and ATP synthesis increased in WT hearts following Ex (+ 22.6-35.1%, p<0.05) as measured in saponin-permeabilized cardiac fibers using pyruvate or palmitoyl carnitine as substrates. In contrast, no difference was observed in CIRS1KO and CIRS2KO following Ex. In isolated perfused working hearts, palmitate oxidation (POX) rates increased in WT hearts following Ex (660.1 ± 122.1 vs. 338.5 ± 37.6 nmol/min/g dhw, p<0.05), while CIRS1KO and CIRS2KO hearts showed no difference compared to Sed. Similarly, glucose oxidation (GLOX) increased in WT hearts following swim training by 2.04fold (p<0.05). This effect was attenuated in CIRS1KO and CIRS2KO (+ 56.8% and +20.6% respectively compared to Sed). Thus, although IRS isoforms play divergent roles in the developmental regulation of cardiac size, both isoforms are specifically required for the hypertrophic and bioenergetics response of the heart to exercise.
- © 2013 by American Heart Association, Inc.