Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 305, Issue 7, Pages E907-E915Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00380.2013
Keywords
skeletal muscle atrophy; growth arrest and DNA damage-inducible 45 alpha; histone deacetylase 4; activating transcription factor 4
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Funding
- National Institutes of Health [1R01-AR-059115-01, 1F30-AG-044964-01]
- Department of Veterans Affairs Biomedical Laboratory Research & Development Service [IBX000976A]
- Fraternal Order of Eagles Diabetes Research Center at the University of Iowa
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Skeletal muscle denervation causes muscle atrophy via complex molecular mechanisms that are not well understood. To better understand these mechanisms, we investigated how muscle denervation increases growth arrest and DNA damage-inducible 45 alpha (Gadd45a) mRNA in skeletal muscle. Previous studies established that muscle denervation strongly induces Gadd45a mRNA, which increases Gadd45a, a small myonuclear protein that is required for denervation-induced muscle fiber atrophy. However, the mechanism by which denervation increases Gadd45a mRNA remained unknown. Here, we demonstrate that histone deacetylase 4 (HDAC4) mediates induction of Gadd45a mRNA in denervated muscle. Using mouse models, we show that HDAC4 is required for induction of Gadd45a mRNA during muscle denervation. Conversely, forced expression of HDAC4 is sufficient to increase skeletal muscle Gadd45a mRNA in the absence of muscle denervation. Moreover, Gadd45a mediates several downstream effects of HDAC4, including induction of myogenin mRNA, induction of mRNAs encoding the embryonic nicotinic acetylcholine receptor, and, most importantly, skeletal muscle fiber atrophy. Because Gadd45a induction is also a key event in fasting-induced muscle atrophy, we tested whether HDAC4 might also contribute to Gadd45a induction during fasting. Interestingly, however, HDAC4 is not required for fasting-induced Gadd45a expression or muscle atrophy. Furthermore, activating transcription factor 4 (ATF4), which contributes to fasting-induced Gadd45a expression, is not required for denervation-induced Gadd45a expression or muscle atrophy. Collectively, these results identify HDAC4 as an important regulator of Gadd45a in denervation-induced muscle atrophy and elucidate Gadd45a as a convergence point for distinct upstream regulators during muscle denervation and fasting.
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