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"Type 5 Adenylyl Cyclase Mechanisms Mediating Cardiac Stress and Exercise Capacity"

by
Lo Lai
Cell Biology and Molecular Medicine Program
B.S. 2005, Wuhan University



Thesis Advisor: Dorothy E. Vatner, M.D.
Professor
Department of Medicine

Tuesday, November 27, 2012
10:00 A.M., MSB E-609


Abstract

Adenylyl cyclase (AC) is a key regulator of health and longevity in organisms ranging from yeast to mammals. Type 5 AC (AC5) is one of two major isoforms in heart. For reasons that remain unclear, whether AC5 is protective or deleterious in response to cardiac stress is controversial, particularly with respect to the signaling mechanisms involved. We show that AC5 regulates MnSOD at the transcriptional level via the Sirt1/FoxO3a pathway, indicating that the susceptibility of the AC5 Tg to cardiomyopathy may be due to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg was completely suppressed by overexpression of MnSOD, whereas the protection afforded by an AC5 knockout was abolished in the context of Mn superoxide dismutase (SOD) heterozygosity (MnSOD+/-). In conclusion, overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering baseline regulation of the Sirt1/FoxO3a, which down-regulates MnSOD expression, resulting in oxidative stress intolerance. These results shed light on new approaches for the prevention and treatment of cardiomyopathies.
Adenylyl cyclase type 5 knockout (AC5 KO) mice have been reported as a new longevity model, which share the similarities in phenotype with caloric restriction (CR). Several CR associated studies in humans demonstrated that long term CR may induce lean muscle loss, thus decrease exercise capacity. We tested our AC5 KO mice for their skeletal muscle phenotype. Surprisingly, AC5 KO mice maintained a similar muscle mass with WT, but contained richer oxidative slow-twitch fibers. Furthermore, AC5 KO mice had enhanced exercise capacity. AC5 KO mice were able to run significantly longer than WT in both distance and time .The gene expression pattern in skeletal muscle of AC5 KO mice was similar to that of the exercise-trained mice. The results demonstrated that inhibition of AC5 is not only beneficial for increasing life span but also maintaining the quality of health.


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