Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

Vatner, Dorothy E.; Yan, Lin; Lai, Lo; Yuan, Chujun; Mouchiroud, Laurent; Pachon, Ronald; Zhang, Jie; Dillinger, Jean‐Guillaume; Houtkooper, Riekelt H.; Auwerx, Johan; Vatner, Stephen F.

doi:10.1111/acel.12401

Cited by 13 publications

(14 citation statements)

References 48 publications

(64 reference statements)

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“…Some of the major mechanisms involved increased SIRT1, mitochondrial biogenesis, protection against oxidative stress and increased nitric oxide, all known to be involved in improved exercise performance. All of these mechanisms have been found to mediate enhanced exercise performance with chronic exercise training [2, 4, 8, 10–12, 29, 31, 32, 36]. …”

Section: Discussionmentioning

confidence: 99%

“…In addition, we measured NOS before and after L-NAME in WT and found decreased NOS by 43%. We have also previously demonstrated that EX527 (10 mg/kg/day) effectively decreases exercise capacity through SIRT1 mediated disruptions in mitochondrial function [31]. In addition, our previous experiments have demonstrated that treatment with L-NAME blocks acetylcholine mediated vasodilator function [15].…”

Section: Methodsmentioning

confidence: 99%

“…We also examined the extent to which 10 days of paraquat treatment (35 mg kg−1, i.p. ), which increases oxidative stress [31], affected the response to exercise in the groups studied. Following our preliminary data additional subsets of animals were added to perform the following biochemical experiments leading to unbalanced samples sizes between figures.…”

Section: Methodsmentioning

confidence: 99%

“…Despite the clear benefits to health, exercise compliance tends to be low and it becomes increasingly difficult to participate in exercise with advancing age, thus making attractive the elucidation of novel mechanisms that offer similar benefits, but can be translated to pharmacological therapy. One potential mechanism is inhibition of adenylyl cyclase type 5 (AC5), since AC5 knockout mice (AC5 KO) exhibit decreased sympathetic tone yet display enhanced exercise capacity [31]. Accordingly it becomes important to compare the enhanced exercise performance in untrained AC5 KO mice with that of exercise training in wild type (WT) mice, and also determine whether the mechanisms mediating both are similar, recognizing the directionally opposite effects on sympathetic tone.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of adenylyl cyclase type 5 mimics exercise training

et al. 2017

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disruption of adenylyl cyclase type 5 mimics exercise training

et al. 2017

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“…Whereas AraA exhibited similar efficacy before and after CAR at the same dose, adenosine required 5 times the dose after CAR to be as effective as AraA or to be as effective as adenosine was when it was administered before CAR. Thus, even though AraA and adenosine share some of the same pathways to mediating cardioprotection (Germack and Dickenson, 2005;Vatner et al, 2015), some of the pathways must be different to explain why AraA exerts more potent protection after CAR.…”

Section: Discussionmentioning

confidence: 99%