Novel mechanisms of proteolytic protein in soleus muscle of hibernating ground squirrels

In mammals, skeletal muscle covers more than 40% of the mass of a given individual and provides key functions in metabolism, energy expenditure, physical strength, and locomotor activity. The skeletal muscle atrophy in response to disuse occurs during bed rest or spaceflight associated with the loss of skeletal muscle mass and the decline in muscle strength and power, muscular activity and cross-sectional muscle area. The soleus muscle (SOL) which is predominantly composed of slow twitch fibers is a postural muscle and more sensitive to disuse than fast-twitch muscles (extensor digitorum longus) and mixture muscles (gastrocnemius). Disuse atrophy results in reduced protein content and a net loss of contractile proteins. A proteomic study on rat soleus muscle after 3-week hindlimb unloading indicates that proteomic responses to disuse had a 0.2- to 0.6-fold decreases in the protein levels of myosin light chain 1 (MLC1), alpha-actin, tropomyosin beta-chain, and troponins T. Moreover, a number of results obtained showed that atrophic changes during a space flight or under head-down bed-rest are accompanied by decrease of total muscle protein and myofibril proteins degradation. Accordingly, disuse atrophy is supposed to be the result of shift of protein synthesis/proteolysis balance towards protein degradation increase. Although 4 catabolic pathways (calpain, ubiquitin-proteasome, autophagy-lysosome and caspase proteolytic pathways) are known to be involved in the atrophy process during disuse, many details remain unknown. A major hindrance to the development of therapeutics to prevent skeletal muscle atrophy under disuse conditions is the lack of understanding of the cellular and molecular mechanisms regulating the loss of muscle mass, especially the change of myofibrillar contents.

The skeletal muscle of hibernators appears to deviate from significant atrophy even after experiencing from extended disuse over three to four months, even six months in the cold North. Hibernators of varying sizes, torpor depths, and life histories (from bears to rodents) may have different mechanisms for emerging from prolonged inactivity with limited disuse atrophy. It has been demonstrated that muscle-fiber number and cross-sectional area were unchanged in gastrocnemius and biceps femoris of hibernating black bears (Ursus americanus), while protein concentration decreased in both muscles during the hibernation period, suggesting only limited muscle atrophy. In addition, it has also been reported that hibernating ground squirrels (Citellus undulatus and Spermophilus dauricus) have an evolutionarily determined adaptive mechanism of preservation or increase of slow fibers ratio, as the most economic and energetically advantageous, with proteins typical of them, whereas hindlimb unloading of non-hibernators (such as mouse) leads to activation of proteolysis and destruction of myofibrillar integrity, which contributes to considerable atrophy of soleus fibers. Atrophy develops early in hibernation in ground squirrels (Spermophilus lateralis), and does not progress in the final 3 months of torpor. Our previous research showed that SOL muscle mass to total body mass ratios (mg/g) were significantly higher in hibernating Daurian ground squirrels compared with that of rats after 14 days of hindlimb suspension, mirroring an effect protecting against disuse atrophy. Daurian ground squirrels (Spermophilus dauricus, Brandt) are obligatory hibernating mammals. They are found across a wide range of latitudes, from steppe and semi-desert and other arid regions of northern China. Daurian ground squirrel hibernation provides a useful model to study mechanisms that increases skeletal muscle resilience against atrophy and dysfunction after extended periods of disuse.

The study on measuring skeletal muscle protein http://www.cusabio.com/ metabolism of bears suggests that protein synthesis and breakdown are both lower in winter compared to summer but are equal during both early and late hibernation periods, indicating that bears are in protein balance during hibernation. Which plays a predominant role in the maintenance of skeletal muscle homeostasis involved in the mechanism of protecting from muscle atrophy during prolonged disuse in hibernation, the increase of protein synthesis or the decrease of protein degradation? It is noteworthy that the protein biosynthesis category by overexpressed genes exhibits a highly significant enrichment in skeletal muscle of hibernating black bears (Ursus americanus). However, serum- and glucocorticoid-inducible kinase 1 (SGK1) can regulates muscle mass maintenance via downregulation of proteolysis and autophagy during hibernation in 13-lined ground squirrels (Ictidomys tridecemlineatus). This is consistent with our previous report demonstrating that inhibition of calpain activity and consequently calpain-mediated protein degradation by highly elevated calpastatin protein expression levels may be an important mechanism for preventing muscle protein loss during hibernation.

Yet researches understand little about myofibrillar contents and relevant synthesis and proteolytic proteins in soleus muscle of hibernating ground squirrels. It is likely that novel mechanisms are involved but are not yet identified. Proteomics approaches are effective at identifying new protein signaling networks. Herein, researchers conducted isobaric tags for relative and absolute quantitation (iTRAQ) proteomics experiments in order to discover hibernation specific skeletal muscle proteomic changes. The study were aimed at 1) to identify differentially expressed proteins between 60-d or 112-d hibernation Daurian ground squirrels relative to the pre-hibernation group; 2) to explore the myofibrillar protein metabolism mechanism underlying the observed anti-atrophy effects in SOL of hibernating ground squirrels with the special ecological environment physiological adaptation.

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