Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle

Daniel Cuthbertson, Kenneth Smith, John Babraj, Graham Leese, Tom Waddell, Philip Atherton, Henning Wackerhage, Peter M. Taylor, Michael J. Rennie

Research output: Contribution to journalArticle

687 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)422-424
Number of pages3
JournalFASEB Journal
Volume19
Issue number3
Early online date13 Dec 2004
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

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Acid resistance
Muscle Proteins
Essential Amino Acids
Muscle
Aging of materials
Amino Acids
Muscles
Insulin
Eukaryotic Initiation Factor-1
Chemical activation
TOR Serine-Threonine Kinases
Maintenance
70-kDa Ribosomal Protein S6 Kinases
Eukaryotic Initiation Factors
Somatotypes
Phosphorylation
Sirolimus
Transcription Factors
Availability
Inflammation

Cite this

Cuthbertson, D., Smith, K., Babraj, J., Leese, G., Waddell, T., Atherton, P., ... Rennie, M. J. (2005). Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB Journal, 19(3), 422-424. https://doi.org/10.1096/fj.04-2640fje
Cuthbertson, Daniel ; Smith, Kenneth ; Babraj, John ; Leese, Graham ; Waddell, Tom ; Atherton, Philip ; Wackerhage, Henning ; Taylor, Peter M. ; Rennie, Michael J. / Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. In: FASEB Journal. 2005 ; Vol. 19, No. 3. pp. 422-424.
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Cuthbertson, D, Smith, K, Babraj, J, Leese, G, Waddell, T, Atherton, P, Wackerhage, H, Taylor, PM & Rennie, MJ 2005, 'Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle', FASEB Journal, vol. 19, no. 3, pp. 422-424. https://doi.org/10.1096/fj.04-2640fje

Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. / Cuthbertson, Daniel ; Smith, Kenneth; Babraj, John; Leese, Graham; Waddell, Tom; Atherton, Philip; Wackerhage, Henning; Taylor, Peter M.; Rennie, Michael J.

In: FASEB Journal, Vol. 19, No. 3, 03.2005, p. 422-424.

Research output: Contribution to journalArticle

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T1 - Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle

AU - Cuthbertson, Daniel

AU - Smith, Kenneth

AU - Babraj, John

AU - Leese, Graham

AU - Waddell, Tom

AU - Atherton, Philip

AU - Wackerhage, Henning

AU - Taylor, Peter M.

AU - Rennie, Michael J.

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N2 - 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.

AB - 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.

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M3 - Article

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