Complex Regulation of HDAC4 in Skeletal Muscle

The study of HDAC4 in denervated muscle also reveals a surprising complexity of its regulation. While it is generally thought that phosphorylated HDAC4 resides in the cytosol, in denervated muscles, HDAC4 is phosphorylated but accumulates in the nucleus. Phosphorylation therefore does not necessarily lead to nuclear export. Despite the robust nuclear accumulation of HDAC4 and its potent repressive activity toward MEF2, denervation is not accompanied by a global shutdown of MEF2-target genes, many of which are structural proteins essential for muscle integrity. In other words, MEF2 target genes are partially protected from the buildup of nuclear HDAC4 induced by denervation. Interestingly, phosphorylation was reported to dissociate HDAC4 from MEF2 independent of HDAC4 nuclear export (McKinsey et al. 2000). It was therefore proposed that phosphorylation of nuclear HDAC4 in denervated muscle might serve to protect muscle from a dramatic loss of MEF2-dependent structural genes (Cohen et al. 2009). A nondiscri-minative repression of MEF2 transcription by nuclear HDAC4 and HDAC5 would lead to severe muscle dysfunction. Indeed, in muscle fibers expressing phosphory-lation-deficient and nuclear-localized HDAC4-3SA mutant, a dramatic reduction in structural genes accompanied by loss of muscle integrity was observed (Cohen et al. 2009). In fact, the skeletal muscle phenotype induced by the HDAC4-3SA mutant is similar to that observed in MEF2C knockout mice (Potthoff et al. 2007b). These studies reveal that phosphorylation of HDAC4 and HDAC5 serves as a critical regulation that protects muscle integrity in response to loss of neural activity. It should be noted that phosphorylated HDAC4, while less active in repressing MEF2 activity, could engage in other signaling events important for muscle remodeling (TJC, MCC and TPY, unpublished observation). In this context, phosphorylation could play an instructive role to redirect HDAC4 to a MEF2-independent pathway.

The mechanism that elicits the transcriptional induction of HDAC4 by denerva-tion remains poorly understood. Although CaMKII or related kinase-mediated phosphorylation could explain the differential phosphorylation and fiber type-selective activity of HDAC4, it is not clear how the same mechanism could affect HDAC4 gene transcription. In addition to calcium-dependent CaMK signaling, denervation also ceases contraction of the muscle. The mechanical contraction of myofibers is believed to have signaling capacity via a kinase titin, which spans half the length of the sarcomeres from the Z-line to the M-line. By sensing the mechanical force generated during contraction, it is thought that titin could regulate the atrophy-promoting E3 ligases MURF1 and MURF2, which are also associated with the sarcomere. Denervation or disease-associated titin mutation causes the dissociation of MURF2 from the sarcomere and entry to the nuclei, resulting in changes in gene transcription (Lange et al. 2005). Interestingly, HDAC4 was also found to associate with the sarcomere in cultured cardiomyocytes (Gupta et al. 2008). The physical interaction of HDAC4 and atrophy-promoting E3 ligases with the contraction apparatus suggests that mechanical contraction might regulate HDAC4 transcription and the muscle atrophy program. If proven correct, HDAC4 would act as a central effector in response to both calcium flux and mechanical force induced by motor neuron activity.

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