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Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age-related sarcopenia^1,2,3

¹ From the University of Nottingham, School of Graduate Entry Medicine and Health, Derby, United Kingdom (EAW, ALS, PJA, RP, DR, KS, and MJR).

² Supported by grants from UK BBSRC (BB/X510697/1, BB/X510697/1, and BB/C516779/1) and from the EC EXEGENESIS program.

³ Address reprint requests and correspondence to MJ Rennie, University of Nottingham, School of Graduate Entry Medicine and Health, Derby City Hospital, Uttoxeter Road, Derby DE22 3DT, United Kingdom. E-mail: michael.rennie{at}nottingham.ac.uk.

Background: Reduced postprandial muscle proteolysis is mainly due to increased insulin availability. Whether rates of proteolysis in response to low physiologic doses of insulin are affected by aging is unknown.

Objectives: We tested the hypothesis that suppression of leg protein breakdown (LPB) by insulin is blunted in older subjects, together with blunted activation of Akt–protein kinase B (PKB).

Design: Groups of 8 young [mean (±SD) age: 24.5 ± 1.8 y] and older (65.0 ± 1.3 y) participants were studied during euglycemic (5 mmol/L), isoaminoacidemic (blood leucine 120 µmol/L) clamp procedures at plasma insulin concentrations of 5 and 15 µIU/mL for 1.5 h. Leg amino acid balance, whole-leg protein turnover (as dilution of amino acid tracers), and muscle protein synthesis were measured with D₅-phenylalanine and [1,2-¹³C₂]leucine. The kinase activity of muscle Akt-PKB and the extent of phosphorylation of signaling proteins associated with the mTOR (mammalian target of rapamycin) pathway were measured before and after the clamp procedures.

Results: Basal LPB rates were not different between groups (66 ± 11 compared with 51 ± 10 nmol leucine · 100 mL leg^–1 · min^–1 and 30 ± 5 compared with 24 ± 4 nmol phenylalanine · 100 mL leg^–1 · min^–1 in young and older groups, respectively). However, although insulin at 15 µIU/mL lowered LPB by 47% in the young subjects (P < 0.05) and abolished the negative leg amino acid balance, this caused only a 12% fall (P > 0.05) in the older group. Akt-PKB activity mirrored decreases in LPB. No differences were seen in muscle protein synthesis or associated anabolic signaling phosphoproteins.

Conclusions: At moderate availability, the effect of insulin on LPB is diminished in older human beings, and this effect may be mediated through blunted Akt-PKB activation.