Prosurvival roles mediated by the PERK signaling pathway effectively prevent excessive endoplasmic reticulum stress‐induced skeletal muscle loss during high‐stress conditions of hibernation

Abstract

Stress conditions like hypoxia, ischemia, and ischemia/reperfusion can trigger excessive endoplasmic reticulum stress (ERS), which can lead to cell apoptosis-induced skeletal muscle atrophy in non-hibernators. However, although hibernators experience multiple stress conditions during hibernation, their skeletal muscles appear to be well protected.We hypothesize that hibernators effectively avoid cell apoptosis, at least partially, by controlling ERS level. Here, we focused on the potential occurrence of ERS and how hibernators cope with it during different hibernation states. Results indicated that the protein expression levels of glucose-regulated protein 78 (GRP78), phosphorylated PKRlike ER protein kinase, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 were significantly increased during hibernation, but primarily recovered in posthibernation. In the torpor-arousal cycle, the expression levels of the above indicators were lower during inter-bout arousal (IBA) than that during late torpor (LT). However, there was no change in C/EBP homologous protein expression and no apoptosis in skeletal muscles during the different hibernation states.In conclusion, the upregulation of p-eIF2α and GRP78 were identified as two crucial mechanisms mediated by the PERK signaling pathway to alleviate elevated ERS. The downregulation of ERS during IBA may be a unique countermeasure for hibernating squirrels to prevent excessive ERS. Thus, these special anti-excessive ERS abilities of ground squirrels contribute to the prevention of skeletal muscle cell apoptosis during hibernation.

Co-activation of Akt, Nrf2, and NF-κB signals under UPRER in torpid Myotis ricketti bats for survival

“…These findings suggest that the PERK/ EIF2/ATF4 signal transduction pathway is activated in torpid bats and that these bats selectively produce some proteins to cope with endoplasmic reticulum stress as seen in many hibernating mammals 51,52 . Since the levels of several UPR ER makers, such as ATF4, PERK, and GRP78, are increased in various tissues (e.g., brain, liver, and muscle) of different mammalian species (e.g., ground squirrels, hamsters, and bats) during hibernation 26,29,[53][54][55] , these findings also support our hypothesis that UPR ER is a common stress response in bats.…”

“…However, the amount of Ser49 p-EIF2α was significantly decreased (P < 0.05) in torpid bats ( Fig. 4e), suggesting that bats translate only certain proteins such as ATF4 during torpor as seen in Daurian ground squirrels 26 . In mice, cold-treated ones had the lowest amount of EIF2α, and the fasted ones had the highest amount of Ser52 p-EIF2α.…”

“…A previous study has shown that UPR ER occurs in the heart of early aroused Syrian hamsters 23 , the brain and brown adipose tissue of torpid thirteen-lined ground squirrels 24,25 , and the skeletal muscles of torpid Daurian ground squirrels 26 . A nearly 20-fold increase in Akt abundance and activation of NF-κB were seen in the gut of hibernating squirrels 27,28 .…”

PERK Overexpression‐Mediated Nrf2/HO‐1 Pathway Alleviates Hypoxia/Reoxygenation‐Induced Injury in Neonatal Murine Cardiomyocytes via Improving Endoplasmic Reticulum Stress

“…Recent studies have provided evidences that several therapies capable of activating PERK cascade exert beneficial roles in improving cellular survival rate. Zhang et al clarify that the upregulation of PERK signaling alleviates apoptosis of skeletal muscle cells under high-stress conditions of hibernation [18]. In addition, data from other studies manifests that the silencing of PERK contributes to the apoptosis of chondrocytes and pancreatic β-cells [19,20].…”

Priority Strategy of Intracellular Ca2+ Homeostasis in Skeletal Muscle Fibers during the Multiple Stresses of Hibernation

“…As described previously [25], immunofluorescence and confocal analyses were used to measure the muscle fiber cross-sectional area (CSA) in frozen sections. Briefly, 10-µm thick frozen cross-sections were cut from the muscle mid-belly at −20 • C with a CM1850 cryostat (Leica, Wetzlar, Germany) and stored at −80 • C until further staining.…”