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Disruption of adenylyl cyclase type 5 mimics exercise training

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Abstract

Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild-type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise-trained WT to levels already attained in untrained AC5 KO. Exercise training in AC5 KO further enhanced their exercise performance. The key difference in untrained AC5 KO and exercise-trained WT was the β-adrenergic receptor signaling, which was decreased in untrained AC5 KO compared to untrained WT but was increased in WT with exercise training. Despite this key difference, untrained AC5 KO and exercise-trained WT mice shared similar gene expression, determined by deep sequencing, in their gastrocnemius muscle with 183 genes commonly up or down-regulated, mainly involving muscle contraction, metabolism and mitochondrial function. The SIRT1/PGC-1α pathway partially mediated the enhanced exercise in both AC5 KO and exercise-trained WT mice, as reflected in the reduced exercise responses after administering a SIRT1 inhibitor, but did not abolish the enhanced exercise performance in the AC5 KO compared to untrained WT. Increasing oxidative stress with paraquat attenuated exercise performance more in untrained WT than untrained AC5 KO, reflecting the augmented oxidative stress protection in AC5 KO. Blocking nitric oxide actually reduced the enhanced exercise performance in untrained AC5 KO and trained WT to levels below untrained WT, demonstrating the importance of this mechanism. These results suggest that AC5 KO mice, without exercise training, share similar mechanisms responsible for enhanced exercise capacity with chronic exercise training, most importantly increased nitric oxide, and demonstrate more reserve with the addition of exercise training. A novel feature of the enhanced exercise performance in untrained AC5 KO mice is their decreased sympathetic tone, which is also beneficial to patients with cardiovascular disease.

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Acknowledgements

We thank Dr. Gopal Babu for generating AC5 floxed mice. We thank Dr. Xiangzhen Sui for her work on the biochemical studies. We thank Dr. Yimin Tian for her work on the histological analyses.

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Authors and Affiliations

  1. Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers University, 185 South Orange Avenue, MSB G609, Newark, NJ, 07103, USA

    John J. Guers, Jie Zhang, Marko Oydanich, Dorothy E. Vatner & Stephen F. Vatner

  2. Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA

    Sara C. Campbell

  3. Department of Medicine, New Jersey Medical School, Rutgers University, 185 South Orange Avenue, MSB G659, Newark, NJ, 07103, USA

    Dorothy E. Vatner

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  1. John J. Guers
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Correspondence to Dorothy E. Vatner or Stephen F. Vatner.

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Conflict of interest

JJG, JZ, SCC, and MO declare that they have no conflict of interest. DEV and SFV have a company involved in developing AC5 inhibitors for cardioprotection. Exercise is not being pursued by this company and this entire study was supported by the NIH grants listed.

Disclosure

Drs. Dorothy and Stephen Vatner have a company involved in developing AC5 inhibitors for cardioprotection. Exercise is not being pursued by this company and this entire study was supported by the NIH grants listed.

Funding resources

This work was supported by National Institute of Health grants P01AG027211, R01HL102472, T32HL069752, P01HL069020, R01HL106511, R01HL093481, R01HL119464, R01HL124282, R01HL106511, and R01HL130848.

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Guers, J.J., Zhang, J., Campbell, S.C. et al. Disruption of adenylyl cyclase type 5 mimics exercise training. Basic Res Cardiol 112, 59 (2017). https://doi.org/10.1007/s00395-017-0648-8

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