Abstract 1625: Type 5 Adenylyl Cyclase Disruption Enhances Exercise Capacity Not Due to Improved Cardiac Output, but Rather to Resistance to Oxidative Stress in Skeletal Muscle
Improving exercise tolerance is one of major goals of physicians treating patients with cardiovascular disease. There are two broad mechanisms by which exercise performance can be enhanced:
an increase in cardiac output (CO);
alterations in energy metabolism in skeletal muscle.
Less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. We examined exercise capacity in type 5 adenylyl cyclase knockout (AC5 KO) mice, which exhibit increased longevity and are protected against stress. The maximal distance run was significantly increased in AC5 KO compared to WT mice (n=13/group) (817±41m vs. 569±26m, p<0.01), and the respiratory exchange ratio at the maximum of exercise (RERmax), an indicator of metabolic substrate utilization, was decreased in the AC5 KO group (0.92±0.02 vs 0.96±0.02; p<0.05). CO, measured with chronically implanted ascending aortic flow probes, increased identically in AC5 KO and WT mice. cDNA microarray revealed genes in skeletal muscle of AC5 KO mice are mainly involved in mitochondrial oxidative metabolism. Enhanced mitochondrial oxidative capacity and biogenesis in skeletal muscle was confirmed, p<0.05, by increased cytochrome C oxidase activity (50%), ATP content (25%), citrate synthase activity (35%), and level of PGC-1alpha (1-fold). It is also known that reduced oxidative stress contributes to increased mitochondrial function. Accordingly, the antioxidant, Tempol (1 mM), administrated to WT mice, improved both distance run and work to exhaustion by 25%, p<0.05. Paraquat, which induces oxidative stress, resulted in 40% less oxidative DNA damage in AC5 KO than in WT mice using 8-OHdG staining. Furthermore, the level of antioxidant MnSOD was significantly increased by 3-fold, p<0.05, in the skeletal muscle of AC5 KO. Mating AC5 KO with MnSOD heterozygous KO mice (n=6) significantly reduced exercise capacity in terms of maximum running distance by 3-fold compared to AC5 KO mice. These results indicate that AC5 inhibition may be a novel approach to improve exercise capacity, not due to improved CO, but rather involving MnSOD mediated resistance to oxidative stress and improved mitochondrial function in skeletal muscle. 1