HDAC4 Is Indispensable for Reduced Slow Myosin Expression at the Early Stage of Hindlimb Unloading in Rat Soleus Muscle.

Inna I Paramonova,Natalia A Vilchinskaya,Boris S Shenkman

doi:10.3390/ph14111167

Inna I Paramonova, Natalia A Vilchinskaya + Show 1 more

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https://doi.org/10.3390/ph14111167

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Abstract

It is well known that reduced contractile activity of the main postural soleus muscle during long-term bedrest, immobilization, hindlimb unloading, and space flight leads to increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC). The signaling cascade such as HDAC4/MEF2-D pathway is well-known to take part in regulating MyHC I gene expression. Earlier, we found a significant increase of HDAC4 in myonuclei due to AMPK dephosphorylation during 24 h of hindlimb unloading via hindlimb suspension (HU) and it had a significant impact on the expression of MyHC isoforms in rat soleus causing a decrease in MyHC I(β) pre-mRNA and mRNA expression as well as MyHC IIa mRNA expression. We hypothesized that dephosphorylated HDAC4 translocates into the nuclei and can lead to a reduced expression of slow MyHC. To test this hypothesis, Wistar rats were treated with HDAC4 inhibitor (Tasquinimod) for 7 days before HU as well as during 24 h of HU. We discovered that Tasquinimod treatment prevented a decrease in pre-mRNA expression of MyHC I. Furthermore, 24 h of hindlimb suspension resulted in HDAC4 nuclear accumulation of rat soleus but Tasquinimod pretreatment prevented this accumulation. The results of the study indicate that HDAC4 after 24 h of HU had a significant impact on the precursor MyHC I mRNA expression in rat soleus.

Highlights

We found a significant increase of HDAC4 in myonuclei due to AMPK dephosphorylation during 24 h of hindlimb unloading via hindlimb suspension (HU) and it had a significant impact on the expression of myosin heavy chain (MyHC) isoforms in rat soleus causing a decrease in MyHC I(β) pre-mRNA and mRNA expression as well as MyHC IIa mRNA
We found that after 24 h of hindlimb unloading via hindlimb suspension, HDAC4 binds directly to MEF2-D, forming a complex, but this complex was not detected in the control group or in the group with Tasquinimod treatment (Figure 5)
The current study showed that after 24 h of hindlimb unloading Tasquinimod treatment prevented a decrease in pre-mRNA expression of MyHC I

Summary

Introduction

It has been discovered that these features of muscle fibers are determined by myosin phenotype, i.e., expression of slow and fast isoforms of myosin heavy chain (MyHC). Gravitational unloading in space flight and simulated microgravity on Earth lead to the myosin phenotype transformation most in the postural soleus muscle—m. It is well known that reduced contractile activity of the main postural soleus muscle during long-term bedrest, immobilization, hindlimb unloading, and space flight leads to increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC) [1,2,3,4,5]. It has been shown that a seven-day spaceflight led to a slow-to-fast shift in the fiber type ratio in soleus rat muscles [6]. It was shown that a decrease in the content of MyHC

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