To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation

Abstract

Mammalian hibernators undergo profound behavioral, physiological, and biochemical changes in order to cope with hypothermia, ischemia-reperfusion, and finite fuel reserves over days or weeks of continuous torpor. Against a backdrop of global reductions in energyexpensive processes such as transcription and translation, a subset of genes/proteins are strategically upregulated in order to meet challenges associated with hibernation. Consequently, hibernation involves substantial transcriptional and posttranscriptional regulatory mechanisms and provides a phenomenon with which to understand how a set of common genes/proteins can be differentially regulated in order to enhance stress tolerance beyond that which is possible for nonhibernators. The present review focuses on the involvement of messenger RNA (mRNA) interacting factors that play a role in the regulation of gene/protein expression programs that define the hibernating phenotype. These include proteins involved in mRNA processing (i.e., capping, splicing, and polyadenylation) and the possible role of alternative splicing as a means of enhancing protein diversity. Since the total pool of mRNA remains constant throughout torpor, mechanisms which enhance mRNA stability are discussed in the context of RNA binding proteins and mRNA decay pathways. Furthermore, mechanisms which control the global reduction of cap-dependent translation and the involvement of internal ribosome entry sites in mRNAs encoding stress response proteins are also discussed. Finally, the concept of regulating each of these factors in discrete subcellular compartments for enhanced efficiency is addressed. The analysis draws on recent research from several well-studied mammalian hibernators including ground squirrels, bats, and bears.

Changes in the phosphoproteome of brown adipose tissue during hibernation in the ground squirrel, Ictidomys tridecemlineatus

“…Microarray analyses of BAT from hibernating squirrels indicated overexpression of genes involved in electron transport and ATP synthesis (40). However, because protein synthesis is strongly turned down during hibernation, mRNA levels will not necessarily correlate with protein expression (34,35).…”

Control of lung ventilation following overwintering conditions in bullfrogs,Lithobates catesbeianus

“…This is an intriguing scenario because prolonged inactivity generally results in loss of function through muscle atrophy or neuroplastic deficits (Clark et al, 2006;Phillips and McGlory, 2014), unless evaded through physiological and/or behavioral compensatory mechanisms. For example, hibernators employ a suite of unique cellular mechanisms to avoid muscle atrophy (Lee et al, 2008;Lin et al, 2012;Nowell et al, 2011;Tessier and Storey, 2014;Van Breukelen and Martin, 2002;Young et al, 2013) and can even experience muscle hypertrophy (Reid et al, 1995). However, some rodent hibernators may also experience skeletal muscle atrophy that should hinder performance (Wickler et al, 1987(Wickler et al, , 1991.…”

Activation of respiratory muscles does not occur during cold-submergence in bullfrogs,Lithobates catesbeianus

“…Broadly speaking, two plausible processes could maintain motor function throughout winter submergence. First, compensatory mechanisms at the cellular level could offset typical degradative processes caused by reduced activity in muscles and neurons as occurs in heterothermic hibernators and silent neural networks (Lee et al, 2008;Lin et al, 2012;Tessier and Storey, 2014;Turrigiano, 2012;Young et al, 2013). Second, the respiratory motor system may avoid the negative influence of inactivity by maintaining neuromotor activation during overwintering submergence.…”