title: Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function inCaenorhabditis elegans.
abstract: Protein aggregation increases with age in normal tissues, and with pathology and age in Alzheimer's hippocampus and mouse cardiac muscle. We now ask whether human skeletal muscle accumulates aggregates with age. Detergent-insoluble protein aggregates were isolated fromvastus lateralisbiopsies from 5 young (23–27 years of age) and 5 older (64-80 years) adults. Aggregates, quantified after gel electrophoresis, contain 2.1-fold more protein (P<0.0001) when isolated from older subjects relative to young. Of 515 proteins identified by liquid chromatography coupled to tandem mass spectrometry, 56 (11%) were significantly more abundant in older muscle, while 21 (4%) were depleted with age (eachP<0.05). Orthologs to seven of these proteins were then targeted inC. elegansby RNA interference. Six of the seven knockdown treatments decreased protein aggregation (range 6-45%,P<0.01 to <0.0001) and increased muscle mass (range 1.5- to 1.85-fold,P<0.01 to <0.0001) in aged nematodes, and rescued mobility (range 1.4 to 1.65-fold,P≤0.0005 each) in a nematode amyloidopathy model. We conclude that specific aggregate proteins, discovered as differentially abundant in aging human muscle, have orthologs that contribute functionally to aggregation and age-associated muscle loss in nematodes, and thus can be considered potential drug targets for sarcopenia in humans.
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.|Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|BioInformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Balasubramaniam
authors.affiliation: Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Suri
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.|Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Sullivan
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.|Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|BioInformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.|Reynolds Institute on Aging, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dennis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans; D055785:Gene Knockdown Techniques; D006801:Humans; D008875:Middle Aged; D009132:Muscles / Q000473:pathology*; D066329:Protein Aggregates; D034622:RNA Interference; D055815:Young Adult
chemical_list: D066329:Protein Aggregates
keywords: aging; protein aggregation; proteostasis; sarcopenia; skeletal muscle