The Response of Muscle Protein Anabolism to Combined Hyperaminoacidemia and Glucose-Induced Hyperinsulinemia Is Impaired in the Elderly

Abstract

Muscle mass declines with aging. Amino acids alone stimulate muscle protein synthesis in the elderly. However, mixed nutritional supplementation failed to improve muscle mass. We hypothesized that the failure of nutritional supplements is due to altered responsiveness of muscle protein anabolism to increased amino acid availability associated with endogenous hyperinsulinemia.We measured muscle protein synthesis and breakdown, and amino acid transport in healthy young (30 ± 3 yr) and elderly (72 ± 1 yr) volunteers in the basal postabsorptive state and during the administration of an amino acid-glucose mixture, using L-[ring-2 H 5 ]phenylalanine infusion, femoral artery and vein catheterization, and muscle biopsies. Basal muscle amino acid turnover was similar in young and elderly subjects. The mixture increased phenylalanine leg delivery and transport into the muscle in both groups. Phenylalanine net balance increased in both groups (young, −27 ± 8 to 64 ± 17; elderly, −16 ± 4 to 29 ± 7 nmol/(min·100 mL); P < 0.0001, basal vs. mixture), but the increase was significantly blunted in the elderly (P = 0.030 vs. young). Muscle protein synthesis increased in the young, but remained unchanged in the elderly [young, 61 ± 17 to 133 ± 30 (P = 0.005); elderly, 62 ± 9 to 70 ± 14 nmol/(min·100 mL) (P = NS)]. In both groups, protein breakdown decreased (P = 0.012) and leg glucose uptake increased (P = 0.0258) with the mixture.We conclude that the response of muscle protein anabolism to hyperaminoacidemia with endogenous hyperinsulinemia is impaired in healthy elderly due to the unresponsiveness of protein synthesis.Muscle mass and function progressively decline with aging (1, 2). This process has been termed sarcopenia and is associated with risk of falls and functional dependence (3,4). Both undernutrition and disuse have been identified as potentially preventable contributing factors (5, 6). Nutritional intervention is an appealing method of prevention and treatment of sarcopenia of the elderly due to its wide applicability and safety. However, attempts to NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript improve muscle mass and strength in the elderly with nutritional supplements failed to demonstrate a beneficial effect (7,8).The failure of nutritional supplementation in the treatment of sarcopenia of the elderly may be due to age-related alterations of muscle protein metabolism in response to feeding. This hypothesis is indirectly supported by recent data in humans suggesting that protein requirements increase with age (9). Increased protein requirements in aging suggest a decline in the ability of old muscle to use and maintain dietary amino acids. Recent studies in old rats have shown that muscle protein synthesis is blunted during balanced feeding (10). In humans, muscle protein synthesis has been found to be slower in elderly compared with young controls during a 5-h meal (11). However, when these data were compared with those obtained in different subjects in the fasting state the st...

Amino acid metabolism and regulatory effects in aging

“…This defect appears associated with the age-related reduction in endotheliumdependent vasodilation [29], and can be reversed by aerobic exercise through improvements in endothelial function and insulin-induced vasodilation, and insulin signaling [30 • ]. These data suggest that vasodilation and nutrient flow to the muscle are important regulators of the muscle anabolic response during hyperinsulinemia [29] and during feeding [13]. This hypothesis is further supported by recent data obtained in young individuals where various levels of physiological hyperinsulinemia were induced in the absence of amino acid replacement [31].…”

“…Second, it is also possible that older adults have a diminished ability to respond to the anabolic effects of the supplements analogous to that observed in old animals. The latter hypothesis is corroborated by the finding that ingestion of an amino acid/glucose mixture stimulated muscle protein synthesis in young, but not older adults [13]. These data have since been confirmed by Guillet et al [28] through the use of a hyperinsulemic/euglycemic clamp while intravenously administering amino acids to emulate the postprandial state.…”

“…Such an imbalance between breakdown and synthesis is smaller in size than that observed in wasting conditions, such as infections or traumatic injuries; however, when protracted over time it can lead to gradual and significant loss of muscle. Since muscle protein degradation has been consistently reported to remain essentially unchanged with advancing age [12][13][14][15][16], there has been an emphasis on studies examining the influence of age on muscle protein synthesis in the basal (postabsorptive) and fed (post-prandial) state. While some researchers have reported a decrease in basal muscle protein synthesis rate with age [17,18], others [14,19] could not confirm those findings in older individuals exhibiting a reduction in muscle mass.…”

Nutrition and sarcopenia: evidence for an interaction

“…Several groups have identified anabolic resistance in human muscle (21)(22)(23)(24)(25) and Rennie's group have reported a blunting of both the stimulation of protein synthesis by amino acids (23) and the inhibition of proteolysis by insulin (25) in the healthy elderly compared with younger adults. This is linked to anabolic signalling deficits which mean that the nutrient signal provided by essential amino acids is not sensed or transduced as well by old muscle as it is by young muscle, resulting in a lower response of protein synthesis to the same nutrient stimulus.…”

Influences of carbohydrate plus amino acid supplementation on differing exercise intensity adaptations in older persons: skeletal muscle and endocrine responses

“…Our data were encouraging in that both levels of exercise were associated with decreased but normal insulin levels (significantly so for SUP_HighR) and these were coupled with fasting glucose effects which also had a potential to indicate increased health (no change in glucose for SUP_HighR, significant decrement for SUP_LowR). Some have suggested the loss of muscle mass commonly associated with the ageing process is a relative resistance to insulin stimulated amino acid uptake and stimulation of muscle protein synthesis (Volpi et al 2000). Insulin itself is a known regulator of protein metabolism.…”