title: Aberrant post-translational modifications compromise human myosin motor function in old age.
abstract: Novel experimental methods, including a modified single fiber in vitro motility assay, X-ray diffraction experiments, and mass spectrometry analyses, have been performed to unravel the molecular events underlying the aging-related impairment in human skeletal muscle function at the motor protein level. The effects of old age on the function of specific myosin isoforms extracted from single human muscle fiber segments, demonstrated a significant slowing of motility speed (P < 0.001) in old age in both type I and IIa myosin heavy chain (MyHC) isoforms. The force-generating capacity of the type I and IIa MyHC isoforms was, on the other hand, not affected by old age. Similar effects were also observed when the myosin molecules extracted from muscle fibers were exposed to oxidative stress. X-ray diffraction experiments did not show any myofilament lattice spacing changes, but unraveled a more disordered filament organization in old age as shown by the greater widths of the 1, 0 equatorial reflections. Mass spectrometry (MS) analyses revealed eight age-specific myosin post-translational modifications (PTMs), in which two were located in the motor domain (carbonylation of Pro79 and Asn81) and six in the tail region (carbonylation of Asp900, Asp904, and Arg908; methylation of Glu1166; deamidation of Gln1164 and Asn1168). However, PTMs in the motor domain were only observed in the IIx MyHC isoform, suggesting PTMs in the rod region contributed to the observed disordering of myosin filaments and the slowing of motility speed. Hence, interventions that would specifically target these PTMs are warranted to reverse myosin dysfunction in old age.
authors: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden; Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors: Meishan
authors: M
authors: Li
authors: Hannah
authors: H
authors: Ogilvie
authors: Julien
authors: J
authors: Ochala
authors: Konstantin
authors: K
authors: Artemenko
authors: Hiroyuki
authors: H
authors: Iwamoto
authors: Naoto
authors: N
authors: Yagi
authors: Jonas
authors: J
authors: Bergquist
authors: Lars
authors: L
authors: Larsson
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D055815:Young Adult
chemical_list: D020033:Protein Isoforms; D009218:Myosins
keywords: aging; function; myosin; post-translational modification; skeletal muscle
references: J Physiol. 1999 Oct 15;520 Pt 2:463-71
references: 10523415
references: J Muscle Res Cell Motil. 2000 May;21(4):357-65
references: 11032346
references: J Mol Biol. 2001 Jan 26;305(4):863-74
references: 11162098
references: Am J Physiol Cell Physiol. 2001 Apr;280(4):C782-8
references: 11245594
references: FASEB J. 2001 Nov;15(13):2415-22
references: 11689466
references: J Mol Biol. 2002 Apr 12;317(5):707-20
references: 11955019
references: Free Radic Biol Med. 2003 Jan 1;34(1):11-22
references: 12498975
references: Gen Physiol Biophys. 1992 Jun;11(3):301-7
references: 1426977
references: Biophys J. 2003 Oct;85(4):2492-506
references: 14507712
references: J Physiol. 2003 Oct 15;552(Pt 2):499-511
references: 14561832
references: Pflugers Arch. 2006 Jul;452(4):464-70
references: 16622703
references: J Appl Physiol (1985). 2006 Dec;101(6):1581-7
references: 16840579
references: Neuromuscul Disord. 2006 Nov;16(11):782-91
references: 17005402
references: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17713-7
references: 17095604
references: J Mol Biol. 2007 Mar 16;367(1):36-41
references: 17254601
references: J Mol Biol. 2007 Aug 24;371(4):902-13
references: 17597155
references: Exp Gerontol. 2009 Jan-Feb;44(1-2):106-11
references: 18657920
references: J Mol Biol. 2009 Jul 3;390(1):99-111
references: 19433094
references: Exp Cell Res. 2010 Jan 1;316(1):115-25
references: 19651121
references: J Physiol. 2010 Dec 15;588(Pt 24):5105-14
references: 20974679
references: FASEB J. 2011 Jun;25(6):1903-13
references: 21350120
references: Free Radic Biol Med. 2011 Oct 15;51(8):1522-32
references: 21810466
references: J Mol Biol. 2011 Dec 9;414(4):477-84
references: 22037585
references: Biochemistry (Mosc). 2011 Dec;76(13):1484-506
references: 22339600
references: Biogerontology. 2013 Jun;14(3):293-301
references: 23681254
references: J Proteomics. 2013 Oct 30;92:63-70
references: 23689083
references: Biosci Biotechnol Biochem. 1992 Jan;56(7):1109-12
references: 27286387
references: Arch Intern Med. 1989 Jul;149(7):1628-33
references: 2742437
references: J Physiol. 1988 Dec;406:85-98
references: 3254423
references: Adv Exp Med Biol. 1988;226:369-80
references: 3261488
references: Age Ageing. 1988 Nov;17(6):365-72
references: 3266440
references: J Am Geriatr Soc. 1987 Jan;35(1):13-20
references: 3794141
references: J Muscle Res Cell Motil. 1984 Apr;5(2):131-46
references: 6144694
references: Methods Enzymol. 1982;85 Pt B:164-81
references: 7121269
references: Prog Neurobiol. 1995 Apr;45(5):397-458
references: 7617890
references: Biochemistry. 1994 Nov 1;33(43):12821-7
references: 7947687
references: Nature. 1993 Sep 30;365(6445):454-6
references: 8413589
references: Acta Physiol Scand. 1993 Feb;147(2):227-34
references: 8475750
references: Am J Physiol. 1996 Jan;270(1 Pt 1):C352-60
references: 8772463
references: Baillieres Clin Endocrinol Metab. 1996 Oct;10(4):469-95
references: 9022947
references: Am J Physiol. 1997 Feb;272(2 Pt 1):C638-49
references: 9124308
references: Muscle Nerve Suppl. 1997;5:S60-4
references: 9331387