Stable atrogin-1 (Fbxo32) and MuRF1 (Trim63) gene expression is involved in the protective mechanism in soleus muscle of hibernating Daurian ground squirrels (Spermophilus dauricus)

Abstract

Understanding the mechanisms that protect against or limit muscle atrophy in hibernators during prolonged inactivity has important implications for its treatment. We examined whether external factors influence the pathways regulating protein synthesis and degradation, leading to muscle atrophy prevention in Daurian ground squirrels (Spermophilus dauricus). We investigated the effects of 14-day hindlimb-unloading (HU) in different seasons and two-month hibernation on the soleus (SOL) muscle wet mass, muscle-to-body mass ratio, fiber cross sectional area (CSA), fiber distribution and muscle ultrastructure. We also measured changes in the protein expression and activation states of Akt, mTOR and FoxO1 and the mRNA expression of atrogin-1 and MuRF1. Compared with the control groups, autumn and winter HU significantly lowered SOL muscle wet mass and muscle-to-body mass ratio, decreased type I and II fiber CSA and induced ultrastructural anomalies. However, these measured indices were unchanged between Pre-hibernation and Hibernation groups. Furthermore, phosphorylation levels of Akt and mTOR significantly decreased, while the phosphorylation level of FoxO1 and mRNA expression of atrogin-1 and MuRF1 increased after HU. During hibernation, the phosphorylation levels of Akt and mTOR significantly decreased, but the phosphorylation level of FoxO1 and mRNA expression of atrogin-1 and MuRF1 remained unchanged. Overall, our findings suggest that disuse and seasonality may not be sufficient to initiate the innate protective mechanism that prevents SOL atrophy during prolonged periods of hibernation inactivity. The stable expression of atrogin-1 and MuRF1 may facilitate to prevent SOL atrophy via controlling ubiquitination of muscle proteins during hibernation.

iTRAQ-based proteomic analysis of myofibrillar contents and relevant synthesis and proteolytic proteins in soleus muscle of hibernating Daurian ground squirrels (Spermophilus dauricus)

“…Sarcomeric structural proteins such as α-actinin, titin, tropomyosin and desmin were not detected proteomic variations in present study, which supported our previous findings that the stable expression of atrogin-1 and MuRF1 may facilitate to prevent SOL atrophy via controlling ubiquitination of muscle proteins during hibernation [20, 21]. However, evidence showed that long-term disuse causes preferential loss of the giant sarcomere protein titin results in altered muscle function via abnormal sarcomeric organization [35].…”

“…However, serum- and glucocorticoid-inducible kinase 1 (SGK1) can regulate muscle mass maintenance via downregulation of proteolysis and autophagy during hibernation in 13-lined ground squirrels ( Ictidomys tridecemlineatus ) [19], which is consistent with our previous report demonstrating that the 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 [15]. Recently, our group reported that the stable expression of atrogin-1 and MuRF1 may facilitate to prevent SOL [20] and extensor digitorum longus [21] muscle atrophy during hibernation. Although more and more regulatory factors involved in the protein metabolism of skeletal muscle during hibernation were found, the detailed mechanisms of protein synthesis and breakdown in hibernation are far from being elucidated.…”

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

“…Multiple studies have documented that skeletal muscle function and locomotor ability are sufficiently preserved across hibernation (Bodine, ; Cotton, ; Fu et al, ; Gao et al, ; Lee et al, ; Lohuis, Harlow, Beck, & Iaizzo, ; Xu et al, ). Our prior research also showed that hibernators display minimal skeletal muscle mass loss and unmodified muscle fiber cross‐sections (Dang et al, ; Gao et al, ). Interestingly, the regulation of skeletal muscle atrophy is muscle‐type specific (Nowell, Choi, & Rourke, ; Reid, Ng, Wilton, & Milsom, ).…”

A robust TDP-43 knock-in mouse model of ALS

“…Wet mass was a relatively simple and preparatory sign for muscle atrophy as also used by others, eg. Goto et al, [28], Dang et al, [19], etc. Furthermore, while the innervation of neuromuscular junctions (NMJ) in the soleus muscle of 3-month old N390D/+ mice appeared to be normal as the +/+ mice (yellow color, Fig.…”