p38^MAPK regulation of transcription factor targets in muscle and heart of the hibernating bat, Myotis lucifugus

Abstract

Mammalian hibernation combines a profound net metabolic rate suppression with the selective up-regulation of key genes whose protein products address specific metabolic needs of the hibernator. The signal transduction pathways and transcription factors involved in regulating hibernation-responsive gene expression are of great interest. The present study suggests an important role for the p38 mitogen-activated protein kinase (p38 MAPK) and selected downstream transcription factors under its control (CREB, ATF-2, Elk-1) in the metabolic response by skeletal muscle during hibernation of little brown bats, Myotis lucifugus. Western blotting was used to quantify both total protein and levels of the phosphorylated, active forms of p38 MAPK, CREB, ATF-2 and Elk-1 in both skeletal muscle and heart of euthermic and hibernating bats. The p38 MAPK pathway was not apparently activated in heart during torpor but skeletal muscle showed strong increases (2.2-11-fold) in the amounts of phosphorylated p38 T180/Y182, CREB S133, ATF-2T69/71 and Elk-1(S383) in the torpid versus aroused state. By contrast both total and phosphorylated levels of Elk-1 in heart were reduced during hibernation to just 30% of the euthermic values. These data implicate p38 MAPK and its transcription factor targets, CREB, ATF-2 and Elk-1 in skeletal muscle maintenance during hibernation.

Mammalian hibernation: differential gene expression and novel application of epigenetic controls

“…Well-developed antioxidant defenses have two key roles in hibernation: (a) long term cytoprotection during prolonged torpor, and (b) defense against high rates of reactive oxygen species generation associated with the huge increase in oxygen consumption that powers thermogenesis during arousal. Strong increases in the levels of the phosphorylated active forms of several other transcription factors (CREB, ATF-2, Elk-1) also occurred during hibernation in skeletal muscle of bats, associated with an activation of the p38 MAPK (Eddy and Storey, 2007).…”

Animal models of enteroaggregativeEscherichia coliinfection

“…TLRs activate potent innate responses by triggering signaling pathways that regulate gene transcription, such as NFκB and MAPK and activate the production of a large repertoire of pro-inflammatory mediators to orchestrate the influx of leukocytes. 27 More specifically, secretion of IL-8 and CXCL1 by enterocytes generates a chemotactic gradient promoting the recruitment of neutrophils to facilitate clearance of bacteria through phagocytosis. 28 Epithelial cells also secrete CCL20 in response to enteric pathogen to enhance infiltration of cells expressing CCR6.…”

Myostatin levels in skeletal muscle of hibernating ground squirrels

“…The transcription factor targets (CREB, ATF-2 and Elk-1) of p38 MAPK also rose, indicating that signaling events are followed by translation of key factors (Eddy and Storey, 2007). A common marker of atrophy, the signaling protein MAFbx, is elevated during hibernation in both the gastrocnemius and plantaris muscle (Rourke et al, 2004b), but the elevation was not associated with atrophy itself, which was puzzling.…”

“…Therefore, the control of protein synthesis and degradation in hibernator muscles is likely pre-transcriptional at the level of cell signaling, via either activation of growth promoting pathways or suppression of catabolic processes. Various signaling candidates have been investigated, for example the AKT/protein kinase B (PKB) signaling pathway (Abnous et al, 2008) and various mitogenactivated protein kinases (MAPKs) (Eddy and Storey, 2007;MacDonald and Storey, 2005). We hypothesized that control of skeletal muscle mass during hibernation of thirteen-lined ground squirrels, Spermophilus tridecemlineatus may be linked to changes in the natural muscle negative regulator, myostatin, and its key downstream signaling molecules, particularly SMAD2.…”