Abstract
We review recent evidence that acetylation and deacetylation of cellular proteins,
including transcription factors and nuclear cofactors, may be involved in the regulation
of muscle mass. The level of protein acetylation is balanced by histone acetyltransferases
(HATs) and histone deacetylases (HDACs) and studies suggest that this balance is perturbed
in muscle wasting. Hyperacetylation of transcription factors and nuclear cofactors
regulating gene transcription in muscle wasting may influence muscle mass. In addition,
hyperacetylation may render proteins susceptible to degradation by different mechanisms,
including intrinsic ubiquitin ligase activity exerted by HATs and by dissociation
of proteins from cellular chaperones. In recent studies, inhibition of p300/HAT expression
and activity and stimulation of SIRT1-dependent HDAC activity reduced glucocorticoid-induced
catabolic response in skeletal muscle, providing further evidence that hyperacetylation
plays a role in muscle wasting. It should be noted, however, that although several
studies advocate a role of hyperacetylation in muscle wasting, apparently contradictory
results have also been reported. For example, muscle atrophy caused by denervation
or immobilization may be associated with reduced, rather than increased, protein acetylation.
In addition, whereas hyperacetylation results in increased degradation of certain
proteins, other proteins may be stabilized by increased acetylation. Thus, the role
of acetylation and deacetylation in the regulation of muscle mass may be both condition-
and protein-specific. The influence of HATs and HDACs on the regulation of muscle
mass, as well as methods to modulate protein acetylation, is an important area for
continued research aimed at preventing and treating muscle wasting.
Abbreviations:
AMPK (AMP-activated protein kinase), CBP (CREB-binding protein), C/EBP (CCAAT/enhancer binding protein), FOXO (Forkhead box O), GCN5 (General control non-depressible 5), GNAT (Gen5-related N-acetyltransferase), HAT (Histone acetyltransferase), HDAC (Histone deacetylase), HIF-1 (Hypoxia-inducible factor-1), HSP90 (Heat shock protein 90), MOZ (Monocytic leukemia zinc-finger protein), MuRF1 (Muscle RING-finger protein 1), NF-kB (Nuclear factor kappa B), PCAF (p300/CBP-associated factor), PGC-1 (Proliferator-activated receptor γ coactivator-1), RB (Retinoblastoma protein), Runx3 (Runt-related transcription factor 3), SIRT (Sirtuin), SV40 (Simian virus 40), TIP 60 (Tat-interactive protein 60kDa), TSA (Trichostatin A), VCP (Valosin-containing protein)Keywords
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References
- Novel aspects on the regulation of muscle wasting in sepsis.Int J Biochem Cell Biol. 2005; 37: 2156-2168
- Protein degradation by the ubiquitin-proteasome pathway in normal and disease states.J Am Soc Nephrol. 2006; 17: 1807-1819
- Pathophysiologic response to severe burn injury.Ann Surg. 2008; 248: 387-401
- Mechanisms of cancer cachexia.Physiol Rev. 2009; 89: 381-410
- Autophagy in health and disease. 3. Involvement of autophagy in muscle atrophy.Am J Physiol Cell Physiol. 2010; 298: C1291-C1297
- Calcineurin signaling and PGC-1α expression are suppressed during muscle atrophy due to diabetes.Biochim Biophys Acta. 2010; 1803: 960-967
- Malnutrition and wasting in renal disease.Curr Opin Clin Nutr Metab Care. 2009; 12: 378-383
- Sepsis-induced myopathy.Crit Care Med. 2009; 37: S354-S367
- ICU-acquired weakness.Chest. 2007; 131: 1541-1549
- Consequences of sarcopenia.Clin Geriatr Med. 2011; 27: 387-399
- Association between muscle strength and metabolic syndrome in older Korean men and women: the Korean longitudinal study on health and aging.Metabolism. 2012; 61: 317-324
- Respiratory weakness is associated with limb weakness and delayed weaning in critical illness.Crit Care Med. 2007; 35: 2007-2015
- Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.N Engl J Med. 2008; 358: 1327-1335
- Ubiquitination, phosphorylation, and acetylation—triple threat in muscle wasting.J Cell Physiol. 2007; 213: 679-689
- The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy.J Neurochem. 2009; 109: 1557-1569
- Dexamethasone upregulates the expression of the nuclear cofactor p300 and its interaction with C/EBPβ in cultured myotubes.J Cell Biochem. 2005; 94: 1058-1067
- Dexamethasone-induced protein degradation in cultured myotubes is p300/HAT dependent.Am J Physiol Regul Integr Comp Physiol. 2007; 292: R337-R344
- Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes.Biochem Biophys Res Commun. 2009; 378: 399-403
- Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle.Am J Physiol Regul Integr Comp Physiol. 2010; 299: R509-R520
- Acetylation: a regulatory modification to rival phosphorylation?.EMBO J. 2000; 19: 1176-1179
- Regulating the regulators: lysine modifications make their mark.Cell. 2003; 112: 11-17
- Structure and chemistry of the p300/CBP and Rtt 109 histone acetyltransferases: implications for acetyltransferase evolution and function.Curr Opin Struct Biol. 2008; 18: 741-747
- Lysine acetylation: codified crosstalk with other posttranslational modifications.Mol Cell. 2008; 31: 449-461
- New nomenclature for chromatin-modifying enzymes.Cell. 2007; 131: 633-636
- Control of muscle development by dueling HATs and HDACs.Curr Opin Genet Dev. 2001; 11: 497-504
- Regulation of distinct biological activities of the NF-kB transcription factor complex by acetylation.J Mol Med. 2003; 81: 549-557
- The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription.Mol Endocrinol. 2005; 19: 2283-2298
- CCAAT/enhancer-binding protein (C/EBP)β is acetylated at multiple lysines. Acetylation of C/EBPβ at lysine 39 modulates its ability to activate transcription.J Biol Chem. 2007; 282: 956-967
- Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α.EMBO J. 2007; 26: 1913-1923
- The structural basis of protein acetylation by the p300/CBP transcriptional coactivator.Nature. 2008; 451: 846-850
- HAT trick: p300, small molecule, inhibitors.Chem Biol. 2010; 17: 417-418
- Histone deacetylases (HDACs): characterization of the classical HDAC family.Biochem J. 2003; 370: 737-749
- The SIRT2 deacetylase regulates autoacetylation of p300.Mol Cell. 2008; 32: 449-455
- Acetylation of Sirt2 by p300 attenuates its deacetylase activity.Biochem Biophys Res Commun. 2008; 375: 576-580
- Regulatory cross-talk between lysine acetylation and ubiquitination: role in the control of protein stability.Bioessays. 2005; 27: 408-415
- Regulation of protein turnover by acetyltransferases and deacetylases.Biochim. 2008; 90: 306-312
- Regulation and destabilization of HIF-1α by ARD1-mediated acetylation.Cell. 2002; 111: 709-720
- Regulation of SV40 large T-antigen stability by reversible acetylation.Oncogene. 2006; 25: 7391-7400
- p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation.Oncogene. 2006; 25: 4147-4154
- Multiple muscle wasting-related transcription factors are acetylated in dexamethasone-treated muscle cells.Biochem Cell Biol. 2012; 90: 200-208
- Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.Nat Cell Biol. 2010; 12: 665-675
- Polyubiquitination of p53 by a ubiquitin ligase activity of p300.Science. 2003; 300: 342-344
- Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2.Nat Cell Biol. 2007; 9: 331-338
- The APC/C and CBP/p300 cooperate to regulate transcription and cell cycle progression.Nature. 2005; 438: 690-695
- Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways.Mol Cell Biol. 2001; 21: 8035-8044
- Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors.J Biol Chem. 2005; 280: 26729-26734
- An acetylation site in the middle domain of Hsp90 regulates chaperone function.Mol Cell. 2007; 25: 151-159
- The balance between acetylation and deacetylation controls Smad7 stability.J Biol Chem. 2005; 280: 21797-21803
- From discovery to the coming generation of histone deacetylase inhibitors.Curr Med Chem. 2003; 10: 2351-2358
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.Nat Rev Cancer. 2006; 6: 38-51
- Trichostatin A enhances acetylation as well as protein stability of ERα through induction of p300 protein.Breast Cancer Res. 2010; 12: R22
- IKKβ/NF-kB activation causes severe muscle wasting in mice.Cell. 2004; 119: 285-298
- Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.Cell. 2004; 117: 399-412
- The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene.Am J Physiol Endocrinol Metab. 2008; 295: E785-E797
- Endogenous muscle atrophy F-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-kappa B.Circ Res. 2011; 109: 161-171
- Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition.Ann Neurol. 2008; 64: 465-470
- HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.Genes Dev. 2007; 21: 2172-2181
- Molecular regulation of muscle cachexia: it may be more than the proteasome.Biochem Biophys Res Commun. 2002; 290: 1-10
- HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination.Oncogene. 2007; 26: 5468-5476
- Involvement of valosin-containing protein, an ATPase co-purified with IkBα and 26S proteasome, in ubiquitin-proteasome-mediated degradation of IkBα.J Biol Chem. 1998; 273: 3562-3573
- Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism.Biochem Biophys Res Commun. 2012; 417: 528-533
- Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, suppresses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription.J Biol Chem. 2004; 279: 51163-51171
- The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats.J Clin Invest. 2008; 118: 868-878
- Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression.J Biol Chem. 2004; 279: 33716-33726
- Specific inhibition of p300-HAT alters global gene expression and represses HIV replication.Chem Biol. 2007; 14: 645-657
- Improved inhibition of the histone acetyltransferase PCAF by an anacardic acid derivative.Bioorg Med Chem. 2010; 18: 5826-5834
- The NF-kB inhibitor curcumin blocks sepsis-induced muscle proteolysis.Mediat Inflam. 2008; 2008: 317851
- Curcumin and muscle wasting—a new role for an old drug?.Nutrition. 2009; 25: 125-129
- p300/CBP-associated factor histone acetyltransferase processing of a peptide substrate. Kinetic analysis of the catalytic mechanism.J Biol Chem. 2000; 275: 1953-1959
- Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor.Chem Biol. 2010; 17: 471-482
- Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.Nature. 2007; 450: 712-716
- The world of resveratrol.Adv Exp Med Biol. 2001; 492: 159-182
- Plant foods and herbal sources of resveratrol.J Agric Food Chem. 2002; 50: 3337-3340
- Mechanism of human SIRT1 activation by resveratrol.J Biol Chem. 2005; 280: 17187-17195
- Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats.Am J Physiol Regul Integr Comp Physiol. 2010; 299: R1572-R1581
- Chemo-preventive properties of trans-resveratrol are associated with inhibition of activation of the IkB kinase.Cancer Res. 2000; 60: 3477-3483
- Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1.Am J Physiol Endocrinol Metab. 2011; 301: E922-E930
- Resveratrol improves health and survival of mice on a high-calorie diet.Nature. 2006; 444: 337-342
- Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α.Cell. 2006; 127: 1109-1122
- Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat.FASEB J. 2011; 25: 3646-3660
- Resveratrol attenuates high-fat diet-induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial β-oxidation.Metabolism. 2011; 60: 1598-1609
- Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents.Metabolism. 2012; 61: 424-433
- Resveratrol: is selectivity opening the key to therapeutic effects?.Metabolism. 2012; 61: 289-290
- The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting Foxo transcription factors.Mol Cell. 2004; 14: 395-403
- Sepsis increases the expression and activity of the transcription factor forkhead box O 1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism.Int J Biochem Cell Biol. 2010; 42: 701-711
- Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle.Autophagy. 2008; 4: 524-526
- The expression and activity of C/EBPβ and δ are upregulated by dexamethasone in skeletal muscle.J Cell Physiol. 2005; 204: 219-226
- C/EBPβ regulates dexamethasone-induced muscle cell atrophy and expression of atrogin-1 and MuRF1.J Cell Biochem. 2011; 112: 1737-1748
- C/EBPβ mediates tumour-induced ubiquitin ligase atrogin-1/MAFbx upregulation and muscle wasting.EMBO J. 2011; 30: 4323-4335
- The transcription factors NF-kB and AP-1 are differentially regulated in skeletal muscle during sepsis.Biochem Biophys Res Commun. 2001; 281: 1331-1336
- NF-kB mediates the protein loss induced by TNF-α in differentiated skeletal muscle myotubes.Am J Physiol Regul Integr Comp Physiol. 2000; 279: R1165-R1170
- Tumor necrosis factor-regulated biphasic activation of NF-kB is required for cytokine-induced loss of skeletal muscle gene products.J Biol Chem. 2003; 278: 2294-2303
- The IkB kinases IKKα and IKKβ are necessary and sufficient for skeletal muscle atrophy.FASEB J. 2009; 23: 362-370
- Stress-dependent regulation of FoxO transcription factors by the Sirt1 deacetylase.Science. 2004; 303: 2011-2015
- Stimulation of Sirt1-regulated FoxO protein function by the ligand-bound vitamin D receptor.Mol Cell Biol. 2010; 30: 4890-4900
- Negative regulation of fork head transcription factor AFX (FOXO4) by CBP-induced acetylation.Int J Mol Med. 2003; 12: 503-508
- Regulation of FoxO activity by CBP/p300-mediated acetylation.Trends Biochem Sci. 2005; 30: 81-86
- Posttranslational modifications control FoxO3 activity during denervation.Am J Physiol Cell Physiol. 2012; 302: C587-C596
- Mammalian SIRT1 represses forkhead transcription factors.Cell. 2004; 116: 551-563
- Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.EMBO J. 2005; 24: 1021-1032
- Regulation of FoxO transcription factors by acetylation and protein-protein interactions.Biochim Biophys Acta. 2011; 1813: 1954-1960
- Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes.Circ Res. 2010; 107: 1-13
- C/EBP DNA binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle.Am J Physiol Regul Integr Comp Physiol. 2002; 282: R439-R444
- Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex.EMBO J. 2003; 22: 2135-2145
- Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5.Proc Natl Acad Sci USA. 2007; 104: 2703-2708
- Acetylation targets mutant huntingtin to autophagosomes for degradation.Cell. 2009; 137: 60-72
- Regulation of E2F-1 after DNA damage by p300-mediated acetylation and ubiquitination.Cell Cycle. 2005; 4: 930-939
- Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases.Proc Natl Acad Sci USA. 2002; 99: 7757-7762
- Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors.Nat Med. 2006; 12: 1147-1150
- The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.J Biol Chem. 2007; 282: 33752-33759
- A histone deacetylase 4/myogenin positive feed back loop coordinates denervation gene induction and suppression.Mol Biol Cell. 2009; 20: 1120-1131
- Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 ubiquitin ligases.Cell. 2010; 143: 35-45
- Exercise-induced histone modifications in human skeletal muscle.J Physiol. 2009; 587.24: 5951-5958
- p300 acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.Am J Physiol Cell Physiol. 2011; 300: C1490-C1501
- Total and myofibrillar protein breakdown in different types of skeletal muscle: effects of sepsis and regulation by insulin.Metabolism. 1989; 38: 634-640
Article info
Publication history
Published online: May 24, 2012
Accepted:
March 29,
2012
Received:
January 23,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
