Abstract
It is known that MuRF-1 and atrogin-1/MAFbx mRNA expression is increased in rat soleus muscle under unloading conditions. We aimed to determine the role of histone deacetylase 1 (HDAC1) in the activation of MuRF-1 and MAFbx expression in rat soleus muscle at the early stage of hindlimb suspension (HS). To this end, male Wistar rats (195–215 g) were divided into 3 groups (n = 8/group): control (C), 3-day HS (HS) and 3-day HS + HDAC1 inhibitor CI-994 (1 mg/kg/day) (HS + CI). Protein content and mRNA expression levels of regulatory molecules were determined by Western-blotting and RT-PCR. CI-994 treatment prevented HS-induced increase in HDAC1 nuclear content. As expected, 3-day HS induced a significant upregulation in MAFbx, MuRF-1 and ubiquitin. CI-994 administration resulted in an attenuation of HS-mediated increase in MAFbx and ubiquitin expression levels but did not affect MuRF-1 expression. A decrease in histone acetyltransferase p300 nuclear content in the HS group was prevented by CI-994 administration. There were no significant differences in the content of phosphorylated anabolic signaling molecules between HS group and HS + CI group. Thus, inhibition of HDAC1 prevented a HS-mediated increase in MAFbx and ubiquitin expression, but did not affect MuRF-1 gene expression.
Highlights
Skeletal muscle is a highly plastic tissue that can adapt its structure and metabolism in response to various conditions
Along with the difference in soleus weight-to-body weight ratio we found a significant difference in the mRNA expression of ubiquitin between the hindlimb suspension (HS) and HS + CI groups (Table 1)
It is interesting to note that in the unloading group with histone deacetylase 1 (HDAC1) inhibition (HS + CI) ubiquitin mRNA expression did not differ from the control level, but was significantly lower than that in the HS group
Summary
Skeletal muscle is a highly plastic tissue that can adapt its structure and metabolism in response to various conditions. Transcription factors, such as forkhead box O (FOXO), cannot enter the nucleus and activate the expression of MuRF-1 and MAFbx thereby preventing/attenuating skeletal muscle atrophy. In recent studies, we found that phosphorylation of the transcription factor FOXO3 as well as transcription factors of the NF-κB signaling pathway did not always prevent an increase in the expression of E3 ubiquitin ligases in the unloaded skeletal muscle[9,10,11]. We hypothesized that HDAC1 activity is able to control of E3 ubiquitin ligases (MuRF-1 and atrogin-1/ MAFbx) mRNA expression in rat soleus muscle at the early stage of unloading. Identification of molecular mechanisms that control the degradation of muscle proteins during mechanical unloading will help to develop a system of pharmacological interventions that could prevent or attenuate skeletal muscle atrophy
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