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.
Highlights
Torpor and multi-day torpor during seasonal hibernation are strategies used by a variety of mammalian species for fuel/energy conservation
To examine the response of the energy-sensing AMPK signaling pathway to daily torpor in gray mouse lemurs, we measured the relative level of p-AMPKa (Thr172) in torpid and aroused lemurs
The current study provides insights into the molecular regulatory network supporting daily torpor in gray mouse lemurs stretching from the energy sensing AMPK pathway to specific downstream processes including gene transcription and mRNA translation
Summary
Torpor and multi-day torpor during seasonal hibernation are strategies used by a variety of mammalian species for fuel/energy conservation. The gray mouse lemur (Microcebus murinus) from Madagascar is one of the few primate species that is able to enter a hypometabolic state to utilize either daily torpor or multi-day hibernation [7]. This primate represents an ideal model for investigating torpor in the context of biomedical research. One common theme of hypometabolism is the coordinated suppression of energy-expensive metabolic processes such as protein synthesis, cell proliferation, and growth, while upregulating pathways required for survival [10]. Studies have shown that various hibernating species achieve this through control at multiple levels including signal transduction, gene expression, and downstream biological processes [3,11]
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