Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

Kale S Bongers; Daniel K Fox; Scott M Ebert; Steven D Kunkel; Michael C Dyle; Steven A Bullard; Jason M Dierdorff; Christopher M Adams

doi:10.1152/ajpendo.00380.2013

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Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

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Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

Kale S Bongers, Daniel K Fox, Scott M Ebert, Steven D Kunkel, Michael C Dyle, Steven A Bullard, Jason M Dierdorff and Christopher M Adams

American journal of physiology: endocrinology and metabolism, Vol.305(7), pp.E907-E915

10/01/2013

DOI: 10.1152/ajpendo.00380.2013

PMCID: PMC3798708

PMID: 23941879

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Abstract

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 45α ( 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 Gadd45 a 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.

histone deacetylase 4

skeletal muscle atrophy

growth arrest and DNA damage-inducible 45α

activating transcription factor 4

Details

Title: Subtitle: Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4
Creators: Kale S Bongers - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Daniel K Fox - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Scott M Ebert - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Steven D Kunkel - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Michael C Dyle - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Steven A Bullard - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Jason M Dierdorff - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Christopher M Adams - Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; and
Resource Type: Journal article
Publication Details: American journal of physiology: endocrinology and metabolism, Vol.305(7), pp.E907-E915
DOI: 10.1152/ajpendo.00380.2013
PMID: 23941879
PMCID: PMC3798708
NLM abbreviation: Am J Physiol Endocrinol Metab
ISSN: 0193-1849
eISSN: 1522-1555
Publisher: American Physiological Society; Bethesda, MD
Language: English
Date published: 10/01/2013
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025569202771

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