| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online February 7, 2006 as doi:10.1096/fj.05-4607fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,1
Departments of
* Kinesiology,
Biological Sciences,
Medicine, and
Surgery, University of Southern California, Los Angeles, California, USA; and
|| Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
1Correspondence: Department of Internal Medicine, Division of Geriatric Medicine, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0460, USA. E-mail: evolpi{at}utmb.edu
SPECIFIC AIMS
We hypothesized that skeletal muscle protein synthesis in the elderly is resistant to the anabolic action of insulin, and that this effect of aging is independent of a normal glucose tolerance. To test this hypothesis, we exposed the muscles of one leg to hyperinsulinemia by infusing insulin in the femoral artery (with a euglycemic clamp as necessary) and measured muscle amino acid and protein turnover with stable isotope methodologies in older and younger healthy, glucose tolerant subjects. This study design prevented the large decrease in blood amino acid concentrations commonly seen with systemic insulin infusion and allowed us to address our specific aim of determining the effect of insulin on muscle protein synthesis in young and older humans.
PRINICIPAL FINDINGS
1. Skeletal muscle protein synthesis is resistant to the anabolic action of insulin in older subjects
We used three different stable isotope methods to estimate muscle protein synthesis: 1) rate of disappearance (Rd) of amino acids across the leg (two-pool model); 2) utilization of amino acids by muscle for protein synthesis (F0,M; three-pool model); 3) direct incorporation of amino acids into mixed muscle proteins (fractional synthetic rate with the precursor-product technique). Insulin delivery to the leg and leg glucose uptake were not different between groups at baseline and during the insulin infusion. Phenylalanine Rd (35±8 vs. 48±9 nmol·min–1·100 mL leg–1) and F0,M (40±8 vs. 58±8 nmol·min–1·100 mL leg–1) were not different between young and old at baseline, respectively (P<0.05). However, during exposure to hyperinsulinemia Rd (77±18 vs. 40±7 nmol·min–1·100 mL leg–1) and F0,M (93±21 vs. 57±12 nmol·min–1·100 mL leg–1) increased only in the young and not in the elderly, respectively (P<0.05). The fractional synthetic rate of muscle protein synthesis also confirmed this finding (Fig. 1
). Therefore, using three different methods to measure muscle protein synthesis, we confirmed that hyperinsulinemia increases protein synthesis in young human skeletal muscle and that older human skeletal muscle is resistant to this effect of insulin.
|
2. The normal increase in blood flow and amino acid delivery to muscle during hyperinsulinemia is blunted in older subjects
Blood flow (mL·min–1·100 mL of leg–1) across the leg was significantly lower in the older subjects both at rest (young: 4.0±0.4, old: 2.6±0.2) and during hyperinsulinemia (young: 6.7±1.3, old: 2.7±0.2) (P<0.01; group effect). Blood flow was increased significantly during insulin infusion in the young subjects (P<0.05), whereas it did not change blood flow in the older subjects. Endothelin-1 concentrations (pg/mL) in the femoral vein were higher (P<0.05) in the older subjects than in the young both at baseline (young: 1.54±0.52, old: 3.53±0.72) and during insulin infusion (young: 0.71±0.28, old: 2.46±0.39), and slightly but significantly decreased with insulin infusion (P<0.05).
As a consequence, amino acid delivery to the muscle (nmol·min–1·100 mL of leg–1) was significantly lower (P<0.05) in the older subjects at baseline (young: 221±25, old: 156±12) and during hyperinsulinemia (young: 338±65, old: 145±8). Amino acid delivery to the muscle increased significantly during insulin infusion in the young subjects (P<0.05), whereas it did not change in the older subjects.
Blood flow was significantly and negatively correlated with endothelin-1 concentrations during insulin infusion (R=–0.6132, P<0.05), but not at baseline (R=–0.4954, P=0.12). There were significant linear and positive relationships between the insulin-induced changes in phenylalanine delivery (R=0.89; P=0.0001), blood flow (R=0.90; P<0.0001), intracellular phenylalanine availability (R=0.94; P<0.0001), insulin delivery (R=0.57;P=0.042), and the changes in muscle protein synthesis in both young and older subjects.
CONCLUSIONS AND SIGNIFICANCE
Our results indicate that muscle protein synthesis is resistant to the anabolic action of insulin in healthy, nondiabetic older humans. Specifically, muscle protein synthesis significantly increased during hyperinsulinemia in the young, whereas there was no effect in the older volunteers. Since muscle protein breakdown did not significantly change in either young or older subjects, the net muscle protein balance became positive only in the young, indicating that a switch from muscle protein catabolism to anabolism occurred only in the younger subjects. Our current results suggest that this age-associated insulin resistance of muscle proteins is the primary reason for the reduced muscle anabolic response to feeding, and this may play an important role in the development of sarcopenia.
The response of muscle protein synthesis to insulin in our subjects was strongly and positively associated with insulin-induced changes in amino acid delivery to the muscle, intracellular amino acid availability, and blood flow, whereas no associations were found with insulin concentrations, delivery, or amino acid concentrations. This suggests that the effects of insulin on human muscle protein synthesis are not only due to a direct stimulation of muscle protein synthesis, but also to indirect changes mediated both by muscle perfusion and amino acid availability. In our experiment, insulin increased leg blood flow in the young, whereas no changes were detected in the older subjects. Differences in the vasodilatory response to insulin were not sufficient to impair glucose uptake in these glucose tolerant subjects, yet they appear to be a strong predictor of the response of muscle protein synthesis and anabolism to insulin. Nonetheless, blood flow was not the only predictor of the protein synthetic response to insulin. Since insulin-stimulated glucose uptake was not different between groups, we can conclude that healthy aging induces a selective insulin resistance of muscle proteins regardless of glucose tolerance, and is probably due, at least in part, to an impaired response of blood vessels to the dilatory effects of insulin. The role of insulin in stimulating blood flow and amino acid delivery in young and old subjects is summarized in Fig. 2
.
|
Our findings may also provide a much needed explanation for the apparently contradictory results previously reported in the literature regarding the mechanisms leading to insulin-induced muscle protein anabolism in young healthy subjects. Specifically, when a systemic insulin infusion is administered to human subjects, blood amino acid concentrations and delivery of amino acids to the muscle are reduced, and muscle protein synthesis is not stimulated. However, when blood amino acid concentrations are maintained using a local insulin infusion (as done in our study) or with amino acid replacement during a systemic insulin infusion, amino acid delivery is increased due to insulin-induced vasodilation, and muscle protein synthesis is stimulated. Future studies are required to determine the specific physiological role of the insulin-induced vasodilation on muscle protein synthesis.
In summary, our data show that muscle protein synthesis does not increase when older human muscle is exposed to local hyperinsulinemia as it does in younger subjects. The overall protein anabolic response to insulin is significantly reduced with age. There was no relationship between the change in amino acid concentration and the change in protein synthesis, but there was a significant positive relationship with changes in blood flow and amino acid availability. This suggests that a reduced vasodilatory response of older human muscle to insulin may play an important role in the reduced anabolic action of insulin. We conclude that protein metabolism is resistant to the anabolic action of insulin in older human skeletal muscle. Future studies are required to identify the cellular mechanisms responsible for the insulin resistance of muscle protein synthesis in aging muscle.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4607fje;
This article has been cited by other articles:
|
|
 |
|
  E. Volpi, D. L. Chinkes, and B. B. Rasmussen Sequential muscle biopsies during a 6-h tracer infusion do not affect human mixed muscle protein synthesis and muscle phenylalanine kinetics Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E959 - E963. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Greenhaff, L. G. Karagounis, N. Peirce, E. J. Simpson, M. Hazell, R. Layfield, H. Wackerhage, K. Smith, P. Atherton, A. Selby, et al. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle Am J Physiol Endocrinol Metab, September 1, 2008; 295(3): E595 - E604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Colman, T. M. Beasley, D. B. Allison, and R. Weindruch Attenuation of Sarcopenia by Dietary Restriction in Rhesus Monkeys J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2008; 63(6): 556 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Manders, R. Koopman, M. Beelen, A. P. Gijsen, W. K. Wodzig, W. H. Saris, and L. J. van Loon The Muscle Protein Synthetic Response to Carbohydrate and Protein Ingestion Is Not Impaired in Men with Longstanding Type 2 Diabetes J. Nutr., June 1, 2008; 138(6): 1079 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Paddon-Jones, K. R Short, W. W Campbell, E. Volpi, and R. R Wolfe Role of dietary protein in the sarcopenia of aging Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1562S - 1566S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.A. Sayer, H.E. Syddall, E.M. Dennison, H.J. Martin, D.I.W. Phillips, C. Cooper, and C.D. Byrne Grip strength and the metabolic syndrome: findings from the Hertfordshire Cohort Study QJM, November 1, 2007; 100(11): 707 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fujita, H. C. Dreyer, M. J. Drummond, E. L. Glynn, J. G. Cadenas, F. Yoshizawa, E. Volpi, and B. B. Rasmussen Nutrient signalling in the regulation of human muscle protein synthesis J. Physiol., July 15, 2007; 582(2): 813 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fujita, B. B. Rasmussen, J. G. Cadenas, M. J. Drummond, E. L. Glynn, F. R. Sattler, and E. Volpi Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling Diabetes, June 1, 2007; 56(6): 1615 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Schrager, E. J. Metter, E. Simonsick, A. Ble, S. Bandinelli, F. Lauretani, and L. Ferrucci Sarcopenic obesity and inflammation in the InCHIANTI study J Appl Physiol, March 1, 2007; 102(3): 919 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fujita, B. B. Rasmussen, J. A. Bell, J. G. Cadenas, and E. Volpi Basal muscle intracellular amino acid kinetics in women and men Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E77 - E83. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R Wolfe The underappreciated role of muscle in health and disease. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 475 - 482. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
