title: Regulation of Torpor in the Gray Mouse Lemur: Transcriptional and Translational Controls and Role of AMPK Signaling.
abstract: The gray mouse lemur (Microcebus murinus) is one of few primate species that is able to enter daily torpor or prolonged hibernation in response to environmental stresses. With an emerging significance to human health research, lemurs present an optimal model for exploring molecular adaptations that regulate primate hypometabolism. A fundamental challenge is how to effectively regulate energy expensive cellular processes (e.g., transcription and translation) during transitions to/from torpor without disrupting cellular homeostasis. One such regulatory mechanism is reversible posttranslational modification of selected protein targets that offers fine cellular control without the energetic burden. This study investigates the role of phosphorylation and/or acetylation in regulating key factors involved in energy homeostasis (AMP-activated protein kinase, or AMPK, signaling pathway), mRNA translation (eukaryotic initiation factor 2α or eIF2α, eukaryotic initiation factor 4E or eIF4E, and initiation factor 4E binding protein or 4EBP), and gene transcription (histone H3) in six tissues of torpid and aroused gray mouse lemurs. Our results indicated selective tissue-specific changes of these regulatory proteins. The relative level of Thr172-phosphorylated AMPKα was significantly elevated in the heart but reduced in brown adipose tissue during daily torpor, as compared to the aroused lemurs, implicating the regulation of AMPK activity during daily torpor in these tissues. Interestingly, the levels of the phosphorylated eIFs were largely unaltered between aroused and torpid animals. Phosphorylation and acetylation of histone H3 were examined as a marker for transcriptional regulation. Compared to the aroused lemurs, level of Ser10-phosphorylated histone H3 decreased significantly in white adipose tissue during torpor, suggesting global suppression of gene transcription. However, a significant increase in acetyl-histone H3 in the heart of torpid lemurs indicated a possible stimulation of transcriptional activity of this tissue. Overall, our study demonstrates that AMPK signaling and posttranslational regulation of selected proteins may play crucial roles in the control of transcription/translation during daily torpor in mouse lemurs.
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Chemistry and Chemical Engineering Department, Royal Military College of Canada, Kingston, ON K7K 7B4, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Surgery & Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Tessier
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Biochemistry Department, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Biggar
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Biology, Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Wu
authors.affiliation: UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy 91800, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Pifferi
authors.affiliation: UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy 91800, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Perret
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: kenneth_storey@carleton.ca.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Storey
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D016565:Cheirogaleidae / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006605:Hibernation / Q000502:physiology; D006657:Histones / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D064348:Torpor; D014158:Transcription, Genetic
chemical_list: D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D006657:Histones; D012333:RNA, Messenger; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; Histone H3; Metabolic rate depression; Posttranslational modification; Ribosomal initiation factors