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The Nuclear Receptor, Nor-1, Induces the Physiological Responses Associated With Exercise.

Authors
  • Goode, Joel M1
  • Pearen, Michael A1
  • Tuong, Zewen K1
  • Wang, Shu-Ching M1
  • Oh, Tae Gyu1
  • Shao, Emily X1
  • Muscat, George E O1
  • 1 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. , (Australia)
Type
Published Article
Journal
Molecular Endocrinology
Publisher
The Endocrine Society
Publication Date
Jun 01, 2016
Volume
30
Issue
6
Pages
660–676
Identifiers
DOI: 10.1210/me.2015-1300
PMID: 27144290
Source
Medline
License
Unknown

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.

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