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HDAC4 regulates muscle fiber type-specific gene expression programs.

Cohen TJ, Choi MC, Kapur M, Lira VA, Yan Z, Yao TP - Mol. Cells (2015)

Bottom Line: The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers.Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers.Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.

ABSTRACT
Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.

No MeSH data available.


Distinct subcellular localization of HDAC4 in slow and fast muscle fibers. HDAC4 localization was determined by immnostaining slow soleus (Sol) and neighboring fast-rich gastrocnemius (GA) muscles. Frozen muscle cross-sections were co-stained with HDAC4 and fast myosin-specific antibodies. GA and Sol muscles are marked as G and S, respectively. DNA is visualized by Hoechst staining.
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f1-molce-38-4-343: Distinct subcellular localization of HDAC4 in slow and fast muscle fibers. HDAC4 localization was determined by immnostaining slow soleus (Sol) and neighboring fast-rich gastrocnemius (GA) muscles. Frozen muscle cross-sections were co-stained with HDAC4 and fast myosin-specific antibodies. GA and Sol muscles are marked as G and S, respectively. DNA is visualized by Hoechst staining.

Mentions: Given that MEF2 is more active in slow/oxidative fibers, we hypothesized that its repressor, HDAC4, would be inactivated in slow/oxidative fibers. Since nuclear export of HDAC4 leads to MEF2 activation, we investigated if HDAC4 shows differential localization in myofibers (Fig. 1). Immuonostaining with an HDAC4-specific antibody revealed a distinct pattern where more cytosolic staining of HDAC4 was observed in the slow/oxidative fiber-enriched soleus (Sol) muscle as opposed to the predominantly nuclear localization of HDAC4 in the adjacent fast/glycolytic fiber-rich gastrocnemius (GA) muscle. This result indicates that HDAC4 mainly resides in the cytosol of slow/oxidative fibers, which would activate MEF2-dependent transcription.


HDAC4 regulates muscle fiber type-specific gene expression programs.

Cohen TJ, Choi MC, Kapur M, Lira VA, Yan Z, Yao TP - Mol. Cells (2015)

Distinct subcellular localization of HDAC4 in slow and fast muscle fibers. HDAC4 localization was determined by immnostaining slow soleus (Sol) and neighboring fast-rich gastrocnemius (GA) muscles. Frozen muscle cross-sections were co-stained with HDAC4 and fast myosin-specific antibodies. GA and Sol muscles are marked as G and S, respectively. DNA is visualized by Hoechst staining.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400309&req=5

f1-molce-38-4-343: Distinct subcellular localization of HDAC4 in slow and fast muscle fibers. HDAC4 localization was determined by immnostaining slow soleus (Sol) and neighboring fast-rich gastrocnemius (GA) muscles. Frozen muscle cross-sections were co-stained with HDAC4 and fast myosin-specific antibodies. GA and Sol muscles are marked as G and S, respectively. DNA is visualized by Hoechst staining.
Mentions: Given that MEF2 is more active in slow/oxidative fibers, we hypothesized that its repressor, HDAC4, would be inactivated in slow/oxidative fibers. Since nuclear export of HDAC4 leads to MEF2 activation, we investigated if HDAC4 shows differential localization in myofibers (Fig. 1). Immuonostaining with an HDAC4-specific antibody revealed a distinct pattern where more cytosolic staining of HDAC4 was observed in the slow/oxidative fiber-enriched soleus (Sol) muscle as opposed to the predominantly nuclear localization of HDAC4 in the adjacent fast/glycolytic fiber-rich gastrocnemius (GA) muscle. This result indicates that HDAC4 mainly resides in the cytosol of slow/oxidative fibers, which would activate MEF2-dependent transcription.

Bottom Line: The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers.Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers.Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.

ABSTRACT
Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.

No MeSH data available.