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

Abstract

As a typical hibernator, the Daurian ground squirrel (Spermophilus dauricus) spends considerable time in a state of reduced activity with prolonged fasting. Despite this, they experience little muscle atrophy and have thus become an interesting anti-disuse muscle atrophy model. The IKKβ/NF-κB signaling pathway is significant to muscle atrophy due to the protein degradation resulting from the upregulation of the E3 ubiquitin ligase MuRF1. The current study showed that the IKKβ/NF-κB signaling pathway and MuRF1 maintained relatively steady mRNA and protein expression levels, with little muscle atrophy observed in the soleus (slow-twitch, SOL) or extensor digitorum longus (fast-twitch, EDL) during hibernation (HIB); however, mRNA expression significantly increased in the SOL and EDL muscle during interbout arousal (IBA), as did the MuRF1 mRNA level in the SOL and MuRF1 protein level in the EDL. Interestingly, the expressions of p50 and MuRF1 significantly increased during HIB in the gastrocnemius (mixed muscle, GAS) and showed moderate atrophy, but dramatically decreased during IBA. Elevated IKKβ and p50 mRNA and protein expression in the cardiac muscle (CM) during HIB did not accompany increased MuRF1 expression or muscle wasting. Importantly, almost all increased or decreased indicators in the tested tissues recovered to pre-hibernation levels after HIB. This is the first study to report on the unexpected regulation of the IKKβ/NF-κB/MuRF1 pathway with remarkable muscle plasticity in Daurian ground squirrels during hibernation. Furthermore, we found that different types of muscles exhibited different strategies to cope with prolonged hibernation-induced disuse muscle atrophy.

Remarkable Protective Effects of Nrf2-Mediated Antioxidant Enzymes and Tissue Specificity in Different Skeletal Muscles of Daurian Ground Squirrels Over the Torpor-Arousal Cycle

“…We detected specific proteins in the tissue homogenates using Western blotting, as described previously (Wei et al, 2018a, b). Total proteins were extracted from the skeletal muscle samples using RIPA lysis (Heart, Xi’an, China).…”

“…Here, we investigated how the antioxidant system in the skeletal muscles of Daurian ground squirrels responds to conditions experienced during the torpor-arousal cycle (e.g., low temperature, fasting, mechanical unloading, and repeated hypoxic ischemia-reperfusion). The SOL muscle consists of slow-twitch oxidative type fibers (i.e., myosin heavy-chain type I, MHC I) (Fu et al, 2016; Wei et al, 2018a), which contain a large number of mitochondria and rely on aerobic oxidation to generate energy. Conversely, the extensor digitorum longus (EDL) muscle consists of fast-twitch glycolytic type fibers (i.e., MHC II) (Fu et al, 2016; Wei et al, 2018a), which contain fewer mitochondria and rely on anaerobic glycolysis to provide energy.…”

“…The SOL muscle consists of slow-twitch oxidative type fibers (i.e., myosin heavy-chain type I, MHC I) (Fu et al, 2016; Wei et al, 2018a), which contain a large number of mitochondria and rely on aerobic oxidation to generate energy. Conversely, the extensor digitorum longus (EDL) muscle consists of fast-twitch glycolytic type fibers (i.e., MHC II) (Fu et al, 2016; Wei et al, 2018a), which contain fewer mitochondria and rely on anaerobic glycolysis to provide energy. The mixed gastrocnemius (GAS) muscle consists of both oxidative and glycolytic type muscle fibers, and thus both aerobic and anaerobic functions (Fu et al, 2016; Wei et al, 2018a).…”

“…Conversely, the extensor digitorum longus (EDL) muscle consists of fast-twitch glycolytic type fibers (i.e., MHC II) (Fu et al, 2016; Wei et al, 2018a), which contain fewer mitochondria and rely on anaerobic glycolysis to provide energy. The mixed gastrocnemius (GAS) muscle consists of both oxidative and glycolytic type muscle fibers, and thus both aerobic and anaerobic functions (Fu et al, 2016; Wei et al, 2018a). Therefore, we examined the levels of ROS (H 2 O 2 and MDA), protein expression and activity of multiple antioxidant enzymes (SODs, CAT, and GPx), and expression of the Nrf2/Keap1 signaling pathway in three different skeletal muscles (SOL, EDL, and GAS) of Daurian ground squirrels during different periods of the torpor-arousal cycle.…”

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

“…Molecular mechanisms lying at the core of muscle mass retention in hibernators have been broadly discussed recently 23,[28][29][30][31][32][33][34][35][36][37][38] . Various mechanisms are suggested to be responsible both for the decrease of atrophy development during torpor and for the activation of protein synthesis and muscle mass retention during arousals.…”