title: Nrf2 modulates contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic atrophy.
abstract: The role of Nrf2 in disease prevention and treatment is well documented; however the specific role of Nrf2 in skeletal muscle is not well described. The current study investigated whether Nrf2 plays a protective role in an STZ-induced model of skeletal muscle atrophy. Modulation of Nrf2 through siRNA resulted in a more robust differentiation of C2C12s, whereas increasing Nrf2 with sulforaphane treatment inhibited differentiation. Diabetic muscle atrophy was not dramatically influenced by Nrf2 genotype, since no differences were observed in total atrophy (all fiber types combined) between WT+STZ and KO+STZ animals. Nrf2-KO animals however illustrated alterations in muscle size of Fast, Type II myosin expressing fibers. KO+STZ animals show significant alterations in myosin isoform expression in the GAST. Similarly, KO controls mimic both WT+STZ and KO+STZ muscle alterations in mitochondrial subunit expression. PGC-1α, a well-established player in mitochondrial biogenesis and myosin isoform expression, was decreased in KO control, WT+STZ and KO+STZ SOL muscle. Similarly, PGC-1α protein levels are correlated with Nrf2 levels in C2C12s after modulation by Nrf2 siRNA or sulforaphane treatment. We provide experimental evidence indicating Nrf2 plays a role in myocyte differentiation and governs molecular alterations in contractile and metabolic properties in an STZ-induced model of muscle atrophy.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Whitman
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.forename: Hongting
authors.initials: H
authors.lastname: Zheng
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D024462:Myosin Type II / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D024462:Myosin Type II
keywords: Atrophy; Metabolism; Myosin; Nrf2; Skeletal muscle
references.citation: Oxid Med Cell Longev. 2012;2012:821936
references.pmid: 23050040
references.citation: J Pineal Res. 2011 Mar;50(2):124-31
references.pmid: 21062351
references.citation: Exp Diabetes Res. 2012;2012:216512
references.pmid: 22645602
references.citation: J Pharmacol Exp Ther. 2010 Apr;333(1):140-51
references.pmid: 20086057
references.citation: J Signal Transduct. 2012;2012:982794
references.pmid: 22175016
references.citation: Am J Pathol. 2006 Jun;168(6):1960-74
references.pmid: 16723711
references.citation: J Appl Physiol (1985). 2009 May;106(5):1650-9
references.pmid: 19246652
references.citation: Nature. 2002 Aug 15;418(6899):797-801
references.pmid: 12181572
references.citation: Toxicol Appl Pharmacol. 2012 Nov 1;264(3):315-23
references.pmid: 23000044
references.citation: Free Radic Biol Med. 2005 Apr 15;38(8):989-1001
references.pmid: 15780757
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Endocrinology. 2006 Jun;147(6):3093-106
references.pmid: 16527841
references.citation: World J Diabetes. 2012 Jan 15;3(1):19-28
references.pmid: 22253942
references.citation: Antioxid Redox Signal. 2012 May 15;16(10):1061-70
references.pmid: 22149292
references.citation: Clin Chem. 2009 Apr;55(4):611-22
references.pmid: 19246619
references.citation: Diabetes. 2004 Apr;53(4):1082-8
references.pmid: 15047625
references.citation: Biotechniques. 2007 Jan;42(1):71-5
references.pmid: 17269487
references.citation: Diabetes. 2011 Nov;60(11):3055-66
references.pmid: 22025779
references.citation: J Muscle Res Cell Motil. 1995 Jun;16(3):237-42
references.pmid: 7559996
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926-30
references.pmid: 7937919
references.citation: Neurotoxicology. 2006 Dec;27(6):1094-100
references.pmid: 16959318
references.citation: Am J Physiol Renal Physiol. 2013 Mar 15;304(6):F808-19
references.pmid: 23136004
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:401-26
references.pmid: 23294312
references.citation: Am J Physiol Cell Physiol. 2004 Oct;287(4):C834-43
references.pmid: 15355854
references.citation: Am J Physiol Cell Physiol. 2002 Nov;283(5):C1376-82
references.pmid: 12372798
references.citation: Eur Respir J. 2002 Apr;19(4):617-25
references.pmid: 11998989
references.citation: Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E591-601
references.pmid: 15100091
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19926-31
references.pmid: 19066218
references.citation: Diabetes. 2011 Feb;60(2):625-33
references.pmid: 21270272
references.citation: N Engl J Med. 2011 Jul 28;365(4):327-36
references.pmid: 21699484