Abstract
Unloading leads to skeletal muscle atrophy via the upregulation of MuRF-1 and MAFbx E3-ligases expression. Reportedly, histone deacetylases (HDACs) 4 and 5 may regulate the expression of MuRF1 and MAFbx. To examine the HDAC-dependent mechanisms involved in the control of E3-ubiquitin ligases expression at the early stages of muscle unloading we used HDACs 4 and 5 inhibitor LMK-235 and HDAC 4 inhibitor Tasqinimod (Tq). Male Wistar rats were divided into four groups (eight rats per group): nontreated control (C), three days of unloading/hindlimb suspension (HS) and three days HS with HDACs inhibitor LMK-235 (HSLMK) or Tq (HSTq). Treatment with LMK-235 diminished unloading-induced of MAFbx, myogenin (MYOG), ubiquitin and calpain-1 mRNA expression (p < 0.05). Tq administration had no effect on the expression of E3-ligases. The mRNA expression of MuRF1 and MAFbx was significantly increased in both HS and HSTq groups (1.5 and 4.0 folds, respectively; p < 0.05) when compared with the C group. It is concluded that during three days of muscle unloading: (1) the HDACs 4 and 5 participate in the regulation of MAFbx expression as well as the expression of MYOG, ubiquitin and calpain-1; (2) the inhibition of HDAC 4 has no effect on MAFbx expression. Therefore, HDAC 5 is perhaps more important for the regulation of MAFbx expression than HDAC 4.
Highlights
There are very few studies focusing on the triggering mechanisms involved in the regulation of protein degradation during the early stages of skeletal muscle unloading
E3 ubiquitin ligases MAFbx and MuRF1 play a significant role in this process
We evaluated whether histone deacetylases (HDACs) 4 and 5 are involved in the regulation of unloading-induced processes of muscle atrophy
Summary
There are very few studies focusing on the triggering mechanisms involved in the regulation of protein degradation during the early stages of skeletal muscle unloading. A majority of the previous studies evaluated the role of nuclear transcription factor FoxO phosphorylation in the regulation of expression of the E3 ubiquitin ligases MAFbx and MuRF1 during unloading. We documented that during muscle unloading increased expression of E3 ubiquitin ligases was accompanied by the activation of some components of the Akt-FoxO pathway while other components were not changed [3,4]. Recent studies suggest that HDACs can directly interact with and regulate the activation of transcription factors [5,6,7] We examined whether these alternative mechanisms are working via HDACs 4 and 5 to regulate the expression of E3 ubiquitin ligases during unloading. TreatmentFwiguitrhe 4L.MEvKal-u2a3ti5onshofowpheodsphaortyrelantedd fFoorxOle3scsoennteintg(Ath),isP3i0n0cnreuaclseea,r wconhtielnet T(Bq) atrnedaMtmYeOnGt had no statisticallymsRiNgAniefixcparnestsieoffne(cCt) (inFisgoulerues m4Bu)s.cles of nontreated control rats (C), rats after 3 days of unloading
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