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.

Impaired hypertrophy in myoblasts is improved with testosterone administration

“…Interestingly, similar morphology, transcript and signalling processes were also observed in cells isolated from aged human muscle [33][34][35] and in whole tissue biopsies [36,37]. Thus, these cells can be used as a representative model to investigate mechanisms of atrophic phenotypes (PD) vs. parental control cells (CON) that display hypertrophic phenotypes [7].…”

Absence of insulin signalling in skeletal muscle is associated with reduced muscle mass and function: evidence for decreased protein synthesis and not increased degradation

“…Future studies should investigate the autophagy pathway further. Cuthbertson et al (2005) reported that the major factor causing loss of muscle mass in ageing-related muscle atrophy is a reduction in protein synthesis rates. These researchers related this decreased protein synthesis to a decreased intramuscular expression and activation (phosphorylation) of signalling proteins.…”

Mediterranean Diet attenuates risk of frailty and sarcopenia: New insights and future directions

“…Dietary protein intake stimulates muscle protein synthesis (MPS) and facilitates postprandial muscle protein accretion [105]. Moreover, the need for more dietary protein with ageing is in part due to a compromised ability to efficiently utilize amino acids for MPS, resulting in a blunted muscle protein synthetic response to an anabolic stimuli, a phenomenon termed anabolic resistance [105,106]. As of consequence, evidence based recommendations for protein intake in older adults have recently been published [107,108].…”