Prolonged periods of skeletal muscle inactivity or mechanical unloading (bed rest, hindlimb unloading, immobilization, spaceflight and reduced step) can result in a significant loss of musculoskeletal mass, size and strength which ultimately lead to muscle atrophy. With advancement in understanding of the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy, several different signaling pathways have been studied to understand their regulatory role in this process. However, substantial gaps exist in our understanding of the regulatory mechanisms involved, as well as their functional significance. This review aims to update the current state of knowledge and the underlying cellular mechanisms related to skeletal muscle loss during a variety of unloading conditions, both in humans and animals. Recent advancements in understanding of cellular and molecular mechanisms, including IGF1-Akt-mTOR, MuRF1/MAFbx, FOXO, and potential triggers of disuse atrophy, such as calcium overload and ROS overproduction, as well as their role in skeletal muscle protein adaptation to disuse is emphasized. We have also elaborated potential therapeutic countermeasures that have shown promising results in preventing and restoring disuse-induced muscle loss. Finally, identified are the key challenges in this field as well as some future prospectives.

No abstract

The underlying mechanisms that hibernators deviated from muscle atrophy during prolonged hibernating inactivity remain elusive. This study tested the hypothesis that the maintenance of intracellular Ca 2+ homeostasis and inhibition of apoptosis would be responsible for preventing muscle atrophy in hibernating Daurian ground squirrels. The results showed that intracellular Ca 2+ homeostasis was maintained in soleus and extensor digitorum longus (EDL) in hibernation and post-hibernation, while cytosolic Ca 2+ was overloaded in gastrocnemius (GAS) in hibernation with a recovery in posthibernation. The Ca 2+ overload was also observed in interbout arousals in all three type muscles. Besides, the Bax/Bcl-2 ratio was unchanged in transcriptional level among pre-hibernation, hibernation and interbout arousals, and reduced to a minimum in post-hibernation. Furthermore, the Bax/ Bcl-2 ratio in protein level was reduced in hibernation but recovered in interbout arousals. Although cytochrome C was increased in GAS and EDL in post-hibernation, no apoptosis was observed by TUNEL assay. These findings suggested that the intracellular Ca 2+ homeostasis in hibernation might be regulated by the cytosolic Ca 2+ overload during interbout arousals, which were likely responsible for preventing muscle atrophy via inhibition of apoptosis. Moreover, the muscle-specificity indicated that the different mechanisms against disuse-induced atrophy might be involved in different muscles in hibernation.Calcium homeostasis is an important aspect to maintain intracellular environment in mammals. Under normal condition, intracellular Ca 2+ concentration is accurately regulated to retain a steady level. However, skeletal muscle disuse (e.g. spaceflight, hind limb unloading and bed rest) leads to the disturbance of intracellular Ca 2+ homeostasis, and mainly exhibits Ca 2+ overload. For instance, the intracellular resting Ca 2+ concentration was significantly elevated by 246% and 215% in rats' soleus (SOL) muscle and gastrocnemius (GAS) muscle, respectively, after 4 weeks of hindlimb immobilization 1 . Meanwhile, the significant increase in intracellular Ca 2+ level was also reported in SOL muscle of hindlimb unloading rats 2 . Similarly, our previous study had reported that the intracellular resting Ca 2+ concentration was increased by 330% in SOL muscle of rats after 14 days of hindlimb suspension 3 . The SOL muscle contains large amounts of slow type fibers (more than 84%), while the portion of fast type fibers in EDL is no more than 12% 4,5 . These findings showed that the slow-twitch muscles (SOL) were more sensitive to disuse than the fast-twitch muscles (EDL) and mixture muscles (GAS), which was closely associated with the higher Ca 2+ sensibility in slow type fibers 6,7 .Intracellular Ca 2+ overload plays an important role in the mechanisms of disuse-induced muscle atrophy. Calcium-activated proteases (calpains), which can be activated by elevated intracellular Ca 2+ concentration,