Protective effects of an inducer of molecular chaperon on disuse skeletal muscle

香叶基香叶内酮(Geranylgeranylacetone，GGA)作为治疗胃溃疡和胃炎的药物已在临床上使用多年。GGA选择性地诱导70 kDa的热休克蛋白(HSP70)，在所有细胞和生物体中，HSPs作为一种适应性反应被暴露在一定的压力下。热休克蛋白作为分子伴侣参与蛋白质的正确折叠和重折叠，从而发挥必要的管家和保护功能。因此，在这项研究中，我们研究了GGA在正常和应激条件下对骨骼肌的影响，例如通过后肢卸载导致的废用性萎缩。分别于给予GGA 0、200、400、600 mg/kg后24小时处死大鼠，分离骨骼肌。在比目鱼肌、腓肠肌、足底肌和趾长伸肌中，剂量增加到600 mg/kg时，HSP72的表达没有进一步增加。当暴露在压力下时，GGA使其他类型的细胞增强HSP70的诱导。此外，我们还研究了在后肢卸载条件下给予GGA后热休克蛋白70的诱导。与对照组相比，萎缩肌肉中HSP72的水平降低，而注射GGA的肌肉中HSP72的水平减弱了后肢卸载状态下HSP70的下降。虽然后肢去负荷会导致肌肉萎缩，但在注射GGA的骨骼肌中，肌原纤维蛋白含量的损失明显较少。这些结果表明，GGA可能表现出不依赖于Hsp70诱导的保护作用。此外，这些观察也可能表明，给予GGA可能是减轻肌肉萎缩的有用工具之一。

Geranylgeranylacetone (GGA) has been used in clinics for many years as a therapeutic agent for gastric ulcer and gastritis. GGA induces 70-kDa heat shock protein (HSP70) selectively, and HSPs are induced as an adaptative response in all cells and organisms upon exposure to a number of stresses. HSPs function as molecular chaperones involved in the correct folding and refolding of proteins, and thereby exert essential housekeeping and protective functions. In this study, we thus investigated the effects of GGA on skeletal muscle under normal and stressful conditions such as disuse atrophy by hindlimb unloading in rats. Skeletal muscles were isolated 24 hours after administration of GGA at 0,200,400 and 600 mg/kg. In soleus, gastrocnemius, plantaris and extensor digitorum longus muscles, increasing the dose up to 600 mg/kg did not result in a further increase in HSP72 expression. GGA primed other types of cells for enhanced induction of HSP70, when exposed to stress. In addition, we investigated the induction of HSP70 after administration of GGA in hindlimb unloading condition. The HSP72 levels decreased in the atrophied muscle compare with control, whereas these values in the GGA administrated muscles attenuated the decrease of HSP70 in hindlimb unloading condition. Although hindlimb unloading resulted in muscle atrophy, the loss of myofibrillar protein content was significantly less in the GGA administrated skeletal muscle. These results suggest that GGA may exhibit protective actions independently of Hsp70 induction. Additionally, these observations may also indicate that the administration of GGA could be one of the useful tools to attenuate muscle atrophy.