title: Type 5 adenylyl cyclase disruption leads to enhanced exercise performance.
abstract: The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Lo
authors.initials: L
authors.lastname: Lai
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Chujun
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Pachon
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Jean-Guillaume
authors.initials: JG
authors.lastname: Dillinger
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D002302:Cardiac Output / Q000235:genetics*; D019069:Cell Respiration; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006321:Heart / Q000502:physiology; D008136:Longevity / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase; D020929:Mitogen-Activated Protein Kinase Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: antioxidant defense; exercise; mitochondrial biogenesis; skeletal muscle; type 5 adenylyl cyclase