title: Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis.
abstract: Age-related loss of muscle mass and strength can be accelerated by impaired recovery of muscle mass following a transient atrophic stimulus. The aim of this study was to identify the mechanisms underlying the attenuated recovery of muscle mass and strength in old rats following disuse-induced atrophy. Adult (9 month) and old (29 month) male F344BN rats underwent hindlimb unloading (HU) followed by reloading. HU induced significant atrophy of the hindlimb muscles in both adult (17-38%) and old (8-29%) rats, but only the adult rats exhibited full recovery of muscle mass and strength upon reloading. Upon reloading, total RNA and protein synthesis increased to a similar extent in adult and old muscles. At baseline and upon reloading, however, proteasome-mediated degradation was suppressed leading to an accumulation of ubiquitin-tagged proteins and p62. Further, ER stress, as measured by CHOP expression, was elevated at baseline and upon reloading in old rats. Analysis of mRNA expression revealed increases in HDAC4, Runx1, myogenin, Gadd45a, and the AChRs in old rats, suggesting neuromuscular junction instability/denervation. Collectively, our data suggests that with aging, impaired neuromuscular transmission and deficits in the proteostasis network contribute to defects in muscle fiber remodeling and functional recovery of muscle mass and strength.
authors.affiliation: VA Northern California Health Care System, Mather, CA 95655, USA.|Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Baehr
authors.affiliation: VA Northern California Health Care System, Mather, CA 95655, USA.|Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA.
authors.forename: Daniel W D
authors.initials: DW
authors.lastname: West
authors.affiliation: VA Northern California Health Care System, Mather, CA 95655, USA.
authors.forename: George
authors.initials: G
authors.lastname: Marcotte
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Marshall
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, USA.
authors.forename: Luis Gustavo
authors.initials: LG
authors.lastname: De Sousa
authors.affiliation: VA Northern California Health Care System, Mather, CA 95655, USA.|Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA.|Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Baar
authors.affiliation: VA Northern California Health Care System, Mather, CA 95655, USA.|Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA.|Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, USA.
authors.forename: Sue C
authors.initials: SC
authors.lastname: Bodine
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D019417:Hindlimb Suspension; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D059748:Proteolysis; D011916:Rats, Inbred F344; D020127:Recovery of Function; D013997:Time Factors
chemical_list: D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex
keywords: aging; anabolic resistance; autophagy; hindlimb unloading; ubiquitin proteasome system
references.citation: J Appl Physiol (1985). 1992 Aug;73(2 Suppl):51S-57S
references.pmid: 1388148
references.citation: PLoS Genet. 2011 Oct;7(10):e1002321
references.pmid: 22022281
references.citation: Int J Biochem Cell Biol. 2013 Oct;45(10):2200-8
references.pmid: 23800384
references.citation: J Biol Chem. 2010 Dec 17;285(51):39597-608
references.pmid: 20940294
references.citation: J Physiol. 2006 Jul 1;574(Pt 1):291-305
references.pmid: 16627569
references.citation: Cell. 2010 Oct 1;143(1):35-45
references.pmid: 20887891
references.citation: Exp Gerontol. 2005 Mar;40(3):227-35
references.pmid: 15763400
references.citation: J Appl Physiol (1985). 2009 Oct;107(4):1172-80
references.pmid: 19661454
references.citation: Curr Opin Clin Nutr Metab Care. 2011 May;14(3):223-9
references.pmid: 21415731
references.citation: Nat Cell Biol. 2013 Jul;15(7):741-50
references.pmid: 23685627
references.citation: Cell Rep. 2014 Sep 11;8(5):1509-21
references.pmid: 25176656
references.citation: Res Nurs Health. 1996 Apr;19(2):133-42
references.pmid: 8606983
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):665-75
references.pmid: 12672458
references.citation: Cell Death Differ. 2004 Apr;11(4):381-9
references.pmid: 14685163
references.citation: J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):M911-6
references.pmid: 14570858
references.citation: Br J Clin Pharmacol. 2013 Mar;75(3):708-15
references.pmid: 22957963
references.citation: Semin Immunopathol. 2010 Dec;32(4):431-6
references.pmid: 20814791
references.citation: J Clin Endocrinol Metab. 2011 Apr;96(4):E633-45
references.pmid: 21270330
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Jun;64(6):618-28
references.pmid: 19351696
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):1807-19
references.pmid: 16738015
references.citation: Biochemistry. 1967 Aug;6(8):2493-9
references.pmid: 6049471
references.citation: Circ Res. 2006 Aug 18;99(4):362-71
references.pmid: 16857966
references.citation: Exp Gerontol. 2015 Apr;64:17-32
references.pmid: 25681639
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2920-6
references.pmid: 19351764
references.citation: J Physiol. 2012 Apr 15;590(8):2035-49
references.pmid: 22351629
references.citation: J Appl Physiol (1985). 1987 Jul;63(1):130-7
references.pmid: 2957349
references.citation: Exp Gerontol. 2009 Jan-Feb;44(1-2):106-11
references.pmid: 18657920
references.citation: FASEB J. 2005 Mar;19(3):422-4
references.pmid: 15596483
references.citation: J Physiol. 2016 Jan 15;594(2):453-68
references.pmid: 26548696
references.citation: J Appl Physiol (1985). 2004 Jul;97(1):243-8
references.pmid: 15033970
references.citation: Front Physiol. 2012 Jul 11;3:260
references.pmid: 22934016
references.citation: Mol Cell. 2010 Oct 22;40(2):238-52
references.pmid: 20965419
references.citation: Trends Endocrinol Metab. 2013 May;24(5):247-56
references.pmid: 23375520
references.citation: Sci Signal. 2014 Feb 25;7(314):ra18
references.pmid: 24570486
references.citation: Skelet Muscle. 2011 Mar 02;1(1):11
references.pmid: 21798089
references.citation: Liver Transpl. 2014 Nov;20(11):1424
references.pmid: 25112655
references.citation: J Appl Physiol (1985). 1998 Jan;84(1):157-63
references.pmid: 9451630
references.citation: J Biol Chem. 2007 Nov 16;282(46):33752-9
references.pmid: 17873280
references.citation: Med Sci Sports Exerc. 2001 Sep;33(9):1477-83
references.pmid: 11528335
references.citation: Aging Cell. 2014 Feb;13(1):92-101
references.pmid: 23941502
references.citation: Nutr Clin Pract. 2014 Apr;29(2):159-70
references.pmid: 24531627
references.citation: Nat Cell Biol. 2005 Mar;7(3):311-8
references.pmid: 15723054
references.citation: Br J Cancer. 2012 Sep 4;107(6):931-6
references.pmid: 22871883
references.citation: FASEB J. 2005 Apr;19(6):644-6
references.pmid: 15677694
references.citation: Exp Gerontol. 2005 Aug-Sep;40(8-9):622-33
references.pmid: 16125351
references.citation: Cell Death Differ. 2006 Mar;13(3):374-84
references.pmid: 16397578
references.citation: J Appl Physiol (1985). 2015 Aug 15;119(4):321-7
references.pmid: 26048973
references.citation: J Cell Physiol. 2014 Nov;229(11):1584-94
references.pmid: 24604615
references.citation: Am J Physiol. 1999 Jan;276(1 Pt 1):C120-7
references.pmid: 9886927
references.citation: Mol Biol Cell. 2009 Feb;20(4):1120-31
references.pmid: 19109424
references.citation: Front Physiol. 2014 Feb 21;5:69
references.pmid: 24600408
references.citation: J Physiol. 2009 Jan 15;587(1):211-7
references.pmid: 19001042
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2125-34
references.pmid: 15961411
references.citation: Ageing Res Rev. 2013 Sep;12(4):898-906
references.pmid: 23948422
references.citation: Acta Physiol (Oxf). 2014 Mar;210(3):628-41
references.pmid: 24251881
references.citation: J Physiol. 2016 Apr 15;594(8):1965-78
references.pmid: 26437581
references.citation: Nat Cell Biol. 2001 Nov;3(11):1014-9
references.pmid: 11715023
references.citation: Am J Pathol. 2007 Aug;171(2):513-24
references.pmid: 17620365
references.citation: Am J Physiol Cell Physiol. 2013 Mar 1;304(5):C422-30
references.pmid: 23220115
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R1015-26
references.pmid: 15919734
references.citation: Curr Opin Clin Nutr Metab Care. 2010 Jan;13(1):34-9
references.pmid: 19898232
references.citation: PLoS One. 2012;7(12):e51238
references.pmid: 23284670
references.citation: J Appl Physiol (1985). 2009 Aug;107(2):438-44
references.pmid: 19520837
references.citation: J Appl Physiol (1985). 2010 Dec;109(6):1628-34
references.pmid: 20864557
references.citation: J Appl Physiol (1985). 2009 Jan;106(1):178-86
references.pmid: 18988763
references.citation: Autophagy. 2010 Oct;6(7):929-35
references.pmid: 20657169