title: The Nuclear Receptor, Nor-1, Induces the Physiological Responses Associated With Exercise.
abstract: Skeletal muscle remodels metabolic capacity, contractile and exercise phenotype in response to physiological demands. This adaptive remodeling response to physical activity can ameliorate/prevent diseases associated with poor diet and lifestyle. Our previous work demonstrated that skeletal muscle-specific transgenic expression of the neuron-derived orphan nuclear receptor, Nor-1 drives muscle reprogramming, improves exercise endurance, and oxidative metabolism. The current manuscript investigates the association between exercise, Nor-1 expression and the role of Nor-1 in adaptive remodeling. We demonstrate that Nor-1 expression is induced by exercise and is dependent on calcium/calcineurin signaling (in vitro and in vivo). Analysis of fatigue-resistant transgenic mice that express Nor-1 in skeletal muscle revealed increased hypertrophy and vascularization of muscle tissue. Moreover, we demonstrate that transgenic Nor-1 expression is associated with increased intracellular recycling, ie, autophagy, involving 1) increased expression of light chain 3A or LC3A-II, autophagy protein 5, and autophagy protein 12 in quadriceps femoris muscle extracts from Tg-Nor-1 (relative to Wild-type (WT) littermates); 2) decreased p62 expression indicative of increased autophagolysosome assembly; and 3) decreased mammalian target of rapamycin complex 1 activity. Transfection of LC3A-GFP-RFP chimeric plasmid demonstrated that autophagolysosome formation was significantly increased by Nor-1 expression. Furthermore, we demonstrated a single bout of exercise induced LC3A-II expression in skeletal muscle from C57BL/6 WT mice. This study, when combined with our previous studies, demonstrates that Nor-1 expression drives multiple physiological changes/pathways that are critical to the beneficial responses of muscle to exercise and provides insights into potential pharmacological manipulation of muscle reprogramming for the treatment of lifestyle induced chronic diseases.
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Goode
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pearen
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Zewen K
authors.initials: ZK
authors.lastname: Tuong
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Shu-Ching M
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Oh
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Emily X
authors.initials: EX
authors.lastname: Shao
authors.affiliation: Institute for Molecular Bioscience (J.M.G., M.A.P., Z.K.T., S.-C.W., T.G.O., E.X.S., G.E.O.M.), The University of Queensland, Queensland 4072, Australia; and QIMR Berghofer Medical Research Institute (M.A.P.), Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D000076222:Mechanistic Target of Rapamycin Complex 1; D019703:Calcineurin; D002118:Calcium; D020123:Sirolimus