Transcriptional activation of muscle atrophy promotes cardiac muscle remodeling during mammalian hibernation

Abstract

Background. Mammalian hibernation in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) is characterized by dramatic changes on a physiological and molecular level. During hibernation, mammalian hearts show a propensity to hypertrophy due to the need for increasing contractility to pump colder and more viscous blood. While cardiac hypertrophy is quite often a process characterized by decompensation, the ground squirrel studied is an excellent model of cardiac plasticity and cardioprotection under conditions of hypothermia and ischemia. The forkhead box O (Foxo) family of proteins and myogenin (MyoG) are transcription factors that control protein degradation and muscle atrophy by regulating the expression of the E3 ubiquitin ligases, MAFbx and MuRF1. These ligases are part of the ubiquitin proteasome system by transferring ubiquitin to proteins and targeting these proteins for degradation. Regulation of Foxo1 and 3a occurs through phosphorylation at different residues. The threonine-24 (Thr-24) and serine-319 (Ser-319) residues on Foxo1, and the Thr-32 residue on Foxo3a are phosphorylated by Akt, leading to cytoplasmic localization of Foxo. We propose that the described mechanism contributes to the changes taking place in cardiac muscle throughout hibernation.Methods. Total and phosphorylated protein levels of Foxo1 and Foxo3a, as well as total protein levels of MyoG, MAFbx, and MuRF1, were studied using immunoblotting.Results. Immunoblotting results demonstrated upregulations in Foxo1 and Foxo3a total protein levels (1.3- and 4.5-fold increases relative to euthermic control, for Foxo1 and 3a respectively) during late torpor, and protein levels remained elevated throughout the rest of torpor and at interbout arousal. We also observed decreases in inactive, phosphorylated Foxo1 and 3a proteins during throughout torpor, where levels of p-Foxo1 Ser319 and Thr24, as well as p-Foxo3a Thr32 decreased by at least 45% throughout torpor. MyoG was upregulated only during late torpor by 2.4-fold. Protein levels of MAFbx and MuRF1 increased in late torpor as well as during early arousal by as much as 2.8-fold, and MAFbx levels remained elevated during interbout arousal, whereas MuRF1 levels returned to control levels.Discussion. The present results indicate that upregulation and activation of Foxo1 and 3a, in addition to the increase in MyoG levels at late torpor, may be upregulating the expression of MAFbx and MuRF1. These findings suggest that there is activation of the ubiquitin proteasome system (UPS) as ground squirrels arouse from torpor. Therefore, the signalling pathway involving MyoG, and the E3 ligases MAFbx and MuRF1, plays a significant role in cardiac muscle remodelling during hibernation. These findings provide insights into the regulation of protein degradation and turnover in the cardiac muscle of a hibernator model.

Waking the sleeping dragon: gene expression profiling reveals adaptive strategies of the hibernating reptile Pogona vitticeps

“…These periods of euthermia allow animals to rewarm and replenish gene and protein products; processes that are virtually halted during torpor [1]. Two decades of molecular studies of hibernation have focused on mammals, such as bears and squirrels [2][3][4][5][6][7][8], and recently marsupials [9], with little consideration of hibernation in reptiles. Debate surrounds the use of the word 'hibernation' in reptiles, with the thought that the lack of active body temperature regulation and inconsistent use of torpor necessitates an alternative term, i.e.…”

“…Hibernators employ general adaptive responses across all tissue types, and exhibit a range of tissue-specific responses. For example, during hibernation neuroprotective processes are activated in the brain (reviewed in [14]), contractive strength is increased in the heart [15,16], and atrophy is limited in skeletal muscle [7,16].…”

Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus)

“…One possible mechanism is that the activation of the NF‐κB signaling pathway promotes downstream target antioxidant enzymes (MnSOD and HO‐1) to protect the organism from oxidative damage induced by hibernation (Allan & Storey, ). The regulation of IKKβ/p50 and MuRF1 against muscle atrophy in skeletal and cardiac muscles is different, suggesting that other signaling pathways, such as FoxO and PPARα, are essential for the regulation of remodeling in CM (Zhang, Aguilar, & Storey, ). Study on distinct cold‐tolerant mechanisms in both cardiac and skeletal muscles in Ictidomys tridecemlineatus suggests that the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, whereas skeletal muscle function and mass are protected through transcriptional regulation of the pathway involved in protein turnover (Vermillion, Anderson, Hampton, & Andrews, ).…”

Predominant synthesis of giant myofibrillar proteins in striated muscles of the long-tailed ground squirrel Urocitellus undulatus during interbout arousal

“…The contents of such ligases as MAFbx and MuRF1, which are part of the ubiquitin proteasome system, increase in the cardiac muscle of thirteen-lined ground squirrels during the early arousal 50 . The content of MAFbx in the heart remains elevated during interbout arousals 50 .…”

“…The contents of such ligases as MAFbx and MuRF1, which are part of the ubiquitin proteasome system, increase in the cardiac muscle of thirteen-lined ground squirrels during the early arousal 50 . The content of MAFbx in the heart remains elevated during interbout arousals 50 . Considering these data 50 , as well as those on the activation of the mTOR complex in striated muscles of thirteen-lined ground squirrels during the early arousal 29 , we assumed that increased autolysis of calpain-1, which leads to enhanced activity of this enzyme, should take place in striated muscles during the interbout arousal.…”