title: Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle.
abstract: The nature of the deficit underlying age-related muscle wasting remains controversial. To test whether it could be due to a poor anabolic response to dietary amino acids, we measured the rates of myofibrillar and sarcoplasmic muscle protein synthesis (MPS) in 44 healthy young and old men, of similar body build, after ingesting different amounts of essential amino acids (EAA). Basal rates of MPS were indistinguishable, but the elderly showed less anabolic sensitivity and responsiveness of MPS to EAA, possibly due to decreased intramuscular expression, and activation (phosphorylation) after EAA, of amino acid sensing/signaling proteins (mammalian target of rapamycin, mTOR; p70 S6 kinase, or p70(S6k); eukaryotic initiation factor [eIF]4BP-1; and eIF2B). The effects were independent of insulin signaling since plasma insulin was clamped at basal values. Associated with the anabolic deficits were marked increases in NFkappaB, the inflammation-associated transcription factor. These results demonstrate first, EAA stimulate MPS independently of increased insulin availability; second, in the elderly, a deficit in MPS in the basal state is unlikely; and third, the decreased sensitivity and responsiveness of MPS to EAA, associated with decrements in the expression and activation of components of anabolic signaling pathways, are probably major contributors to the failure of muscle maintenance in the elderly. Countermeasures to maximize muscle maintenance should target these deficits.
authors.affiliation: Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cuthbertson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.forename: John
authors.initials: J
authors.lastname: Babraj
authors.forename: Graham
authors.initials: G
authors.lastname: Leese
authors.forename: Tom
authors.initials: T
authors.lastname: Waddell
authors.forename: Philip
authors.initials: P
authors.lastname: Atherton
authors.forename: Henning
authors.initials: H
authors.lastname: Wackerhage
authors.forename: Peter M
authors.initials: PM
authors.lastname: Taylor
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rennie
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D000601:Amino Acids, Essential / Q000008:administration & dosage / Q000378:metabolism*; D002247:Carbon Isotopes; D004326:Drinking; D004351:Drug Resistance; D039642:Eukaryotic Initiation Factors / Q000032:analysis; D006801:Humans; D007651:Keto Acids / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007700:Kinetics; D007930:Leucine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology*; D016328:NF-kappa B / Q000032:analysis; D011494:Protein Kinases / Q000032:analysis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis; D015398:Signal Transduction; D012996:Solutions; D058570:TOR Serine-Threonine Kinases
chemical_list: D000601:Amino Acids, Essential; D002247:Carbon Isotopes; D039642:Eukaryotic Initiation Factors; D007651:Keto Acids; D009124:Muscle Proteins; D016328:NF-kappa B; D012996:Solutions; C013082:alpha-ketoisocaproic acid; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine