Journal of Nutrition Animal Diets/Enrichment Products...

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Paddon-Jones, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paddon-Jones, D.
© 2006 American Society for Nutrition J. Nutr. 136:2123-2126, August 2006

Recent Advances in Nutritional Sciences

Interplay of Stress and Physical Inactivity on Muscle Loss: Nutritional Countermeasures1,2

Douglas Paddon-Jones*

The University of Texas Medical Branch, Galveston, TX 77550

* To whom correspondence should be addressed. E-mail: djpaddon{at}utmb.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Summary
 LITERATURE CITED
 
Inactivity-mediated protein catabolism occurs in many circumstances ranging from catastrophic events such as severe illness or injury, to unique environments such as spaceflight/microgravity, to more insidious causes such as physical frailty and the progression of aging. Nevertheless, regardless of the etiology, the consequences of inactivity are readily observable and debilitating. Mechanistically, the loss of lean body mass during inactivity is the result of a chronic imbalance between muscle protein synthesis and breakdown. When inactivity is accompanied by the stress of trauma or disease, the rate of muscle protein catabolism can increase several fold. Bed rest studies in healthy volunteers provide a unique opportunity to examine the mechanisms contributing to muscle loss and evaluate strategies for intervention that may slow muscle catabolism and promote anabolism. The prerequisite for muscle protein synthesis and the most readily adaptable stimulus is dietary-derived amino acids. This review focuses on the role of amino acid supplementation in the maintenance of skeletal muscle mass during age-related and clinically mandated inactivity.


   Introduction
TOP
 ABSTRACT
 Introduction
Summary
 LITERATURE CITED
 
The loss of skeletal muscle mass and functional capacity are undesirable yet inherent consequences of physical inactivity. Inactivity-mediated protein catabolism occurs in many circumstances ranging from catastrophic events such as severe illness or injury, to unique environments such as spaceflight/microgravity, to less overt causes such as physical frailty and the progression of aging. Regardless of the etiology, the consequences of inactivity are readily observable and debilitating. Nevertheless, the question remains: is this catabolic progression avoidable?

Mechanistically, the loss of lean body mass during inactivity is the result of a chronic imbalance between muscle protein synthesis and breakdown. This imbalance can be exacerbated during periods of stress. The stress response most commonly associated with illness or trauma entails the inherent loss of homeostatic balance including increases in circulating concentrations of cortisol, epinephrine, and glucagon (1–6), which can increase the rate of muscle protein catabolism several fold (3,7).

Although clinical studies can provide detailed information on morphological and functional changes associated with pathological conditions such as burn injury or orthopedic trauma (4,8–13), bed rest studies in healthy volunteers provide a unique means of isolating and examining many of the specific mechanisms contributing to muscle loss. Further, the bed rest model provides a unique opportunity to evaluate interventional strategies that may slow muscle catabolism and promote anabolism.

Muscle deposition occurs in response to a complex interplay of stimuli such as physical activity and hormonal signaling (e.g., testosterone, insulin, growth hormone, insulin-like growth factors). However, in all circumstances, the prerequisite for muscle protein synthesis and the most readily adaptable stimulus is dietary-derived amino acids. Therefore, this review will focus on the role of amino acid supplementation in the maintenance of skeletal muscle mass during age-related and clinically mandated inactivity.

    Amino acid supplementation during inactivity. Physical interventions such as exercise clearly provide a potent anabolic stimulus (14,15). However, exercise may not be feasible in situations in which inactivity is the result of injury or illness. Consequently, there is a need to identify alternate or complementary interventions, such as nutrition, that may slow the catabolic process.

We demonstrated recently that ingestion or infusion of essential amino acids (EAA) provides a potent acute anabolic stimulus in healthy young and elderly subjects (16–18). Furthermore, EAA stimulate muscle protein anabolism to a greater degree than a common liquid meal replacement (19), (Fig. 1), or an isocaloric serving of whey protein (20).


Figure 1
View larger version (8K):
[in this window]
[in a new window]
  		Figure 1  Net phenylalanine balance across the leg during a postabsorptive/fasting period and for 2.5 h after ingestion of a mixed-nutrient meal or EAA supplement in healthy young men on d 1 and 28 of bed rest. Values are means ± SEM, n = 7. *Different from mixed-meal ingestion, P < 0.05; {ddagger}different from fasting values, P < 0.05. Adapted from Paddon-Jones et al. (19).

 
Given these positive acute metabolic study results, we hypothesized that dietary amino acid supplementation would also provide an effective means of ameliorating muscle loss associated with prolonged inactivity. Our hypothesis was based on the fact that EAA administration stimulates muscle protein synthesis, the primary defect in muscle protein metabolism, during inactivity. The decision to use EAAs was further supported by the fact that dietary EAA supplements are easy to administer, the cost is relatively low, they can be used in almost all populations and in conjunction with other therapies, and they are intuitively and theoretically appropriate.

To test our hypothesis, we conducted a 28-d bed rest study using a cohort of 13 healthy young men (21). In additional to controlled mixed-nutrient meals, the subjects were randomly assigned to receive either a placebo (n = 6) or an EAA plus carbohydrate supplement (n = 7) 3 times/d during 28 d of bed rest. The results indicated that the initial stimulatory effect of EAA supplementation was cumulative; specifically, EAA supplementation stimulated muscle protein synthesis on d 1 of bed rest and remained anabolic throughout 28 d of bed rest (21). In contrast, a standard mixed meal containing ~35 g of intact protein provided minimal anabolic stimulus in the absence of physical activity (21).

The repeated stimulation of net muscle protein synthesis afforded by EAA ingestion translated to a maintenance of lean body mass and the partial preservation of strength after 28 d of inactivity (Fig. 2). Further, it is likely that EAA supplementation conferred a direct anabolic effect, and the maintenance of muscle mass and strength was not due simply to additional energy intake. This is largely based on the fact that fat or carbohydrate ingestion alone does not promote protein anabolism. Further, the acute anabolic response to EAA ingestion was ~10-fold greater than the response to the standard mixed meal.


Figure 2
View larger version (12K):
[in this window]
[in a new window]
  		Figure 2  Change in lean leg mass (DEXA) and one repetition maximum leg extension strength after 28 d of bed rest in healthy young men. Values are means ± SEM, n = 7. #Significant reduction, P < 0.05; *different from placebo, P < 0.05. Adapted from Paddon-Jones et al. (21).

 
Although it is tempting to speculate that this simple EAA intervention may also ameliorate the loss of lean body mass in clinical populations, it is most likely not a singular solution. Nevertheless, in frail, aging populations or following trauma or illness, EAA supplementation used in conjunction with existing exercise/rehabilitation regimens offers great promise.

    Amino acid supplementation and aging. Sarcopenia is an insidious process characterized in part by the progressive loss of muscle mass and functional capacity. Sarcopenia is all too common, with 16% of men and 12% of women aged 70–79 y likely to experience muscle loss and associated functional limitations (22). This is further exacerbated by the higher incidence of several pathologic conditions in aging populations. For example, 75% of hip fracture patients will lose so much muscle mass that they never regain their previous level of function (23). Further, in patients hospitalized with chronic heart failure, 50–68% will experience cardiac cachexia due to disease progression and malnutrition (24,25).

In the absence of associated injury or illness, sarcopenia is likely facilitated by a combination of factors including the adoption of a more sedentary lifestyle and a less than optimal diet (26–28). A large percentage of homebound elderly consume <0.7 g mixed protein/(kg·d), well below the recommended daily intake of 0.8 g/(kg·d), which itself could be considered a minimal requirement (29). Understandably, the first instinct of many clinicians attempting to correct the protein-energy deficit is to simply add protein to the diet. Extensive trials with protein supplementation were conducted in attempts to ameliorate the debilitating progression of sarcopenia (30–32). Unfortunately, although nutritional supplementation is often necessary, a simple increase in total energy intake may not effectively reduce catabolism or promote muscle anabolism in the elderly. In some earlier studies, it was noted that when a nutritionally mixed supplement was given, total energy intake decreased by a reciprocal amount (30). In other words, the elderly consumed the supplement but, perhaps due to increased satiety, adjusted their total energy intake accordingly (33). Thus, to be effective, a supplement must at least be capable of stimulating net muscle protein synthesis to the same extent as conventional dietary protein, and should not interfere with subsequent meal intake. Fortunately, with EAA supplementation, this seems to be the case (19). In the elderly, we demonstrated that EAA supplementation is capable of stimulating net muscle protein synthesis to a greater degree than a traditional high-quality protein supplement (Fig. 3) and that this anabolic effect is independent of insulin response (20). Further, in a cohort of young volunteers, we demonstrated that the anabolic response to an EAA supplement does not diminish the subsequent anabolic response to a meal when separated by only 3 h (19). Thus, given the positive supporting evidence and practical viability, amino acids may provide an effective means of promoting muscle anabolism in aging populations.


Figure 3
View larger version (11K):
[in this window]
[in a new window]
  		Figure 3  Muscle protein synthesis (FSR) before and after ingestion of 15 g EAA (n = 7) or 15 g WY protein (n = 7) in healthy elderly volunteers. Values are means ± SEM. {dagger}EAA and Whey differ, P < 0.05. *Different from fasting values, P < 0.05. Adapted from Paddon-Jones et al. (20).

 
    Inactivity and stress. Skeletal muscle loss is one of the most phenotypically obvious consequences of chronic illness and disease. The physiological consequences can be devastating when prolonged inactivity is combined with an insult such as orthopedic trauma or burn injury (1,2). The loss of lean body mass in these clinical populations is facilitated and amplified by increased circulating concentrations of the counterregulatory hormones epinephrine, norepinephrine, glucagon, and cortisol. The increase in the concentration of these hormones is, in turn, generally proportional to the severity of the injury (2,4,34). Although each of the counterregulatory hormones plays a role in the initial phase of metabolic deregulation (35), it appears that a chronic elevation in plasma cortisol is a primary hormonal stimulus for muscle protein catabolism. In an early study examining whole-body nitrogen balance, Gelfand et al. (35) noted that while exogenously induced hypercortisolemia had a minimal effect on nitrogen loss during the first 3 d of administration, the catabolic effects increased markedly thereafter and were similar to the combined effects of exogenous catecholamine and glucagon administration.

Our laboratory also demonstrated a catabolic interaction between inactivity and hypercortisolemia (4). Young subjects were challenged with 12 h of hypercortisolemia before and after 14 d of bed rest (Fig. 4). Cortisol was infused over this period to mimic the blood concentrations observed after severe trauma (e.g., ~910 nmol/L). The hypercortisolemic challenge before inactivity did not produce any greater muscle catabolism than fasting alone. However, after 14 d of inactivity, the same cortisol challenge increased protein breakdown and negatively affected net muscle protein balance. Specifically, inactivity appears to facilitate the deleterious catabolic response to hypercortisolemia. Fortunately, recent evidence suggests that the acute anabolic response to amino acid ingestion is not impaired by concurrent hypercortisolemia (27). These data raise the possibility of successfully using amino acids as a countermeasure for muscle loss associated with longer-term periods of stress or inactivity including hospitalization and convalescence after injury or illness.


Figure 4
View larger version (10K):
[in this window]
[in a new window]
  		Figure 4  Change in lean muscle mass following bed rest with chronic hypercortisolemia (n = 6), (Paddon-Jones, unpublished observation). Values are means ± SEM. {dagger}Significant decrease, P < 0.05. For comparison, the loss of lean leg mass after 28 d of bed rest alone is also presented (n = 6). Adapted from Paddon-Jones et al. (21).

 

   Summary
TOP
 ABSTRACT
 Introduction
 Summary
LITERATURE CITED
 
Periods of prolonged inactivity are inherent in many conditions associated with the loss of lean muscle mass. In aging populations, the progression of sarcopenia is intimately associated with the gradual loss of functional capacity and metabolic reserve. This progressive loss of lean tissue is exacerbated in individuals after inactivity associated with trauma or disease. In these instances, muscle protein catabolism is accelerated by the combined deleterious effects of muscular inactivity, a generalized stress response and associated increase in counterregulatory hormone concentrations. We demonstrated that EAA supplementation acutely stimulates muscle protein synthesis in elderly subjects and in young volunteers with and without accompanying hypercortisolemia. The increase in protein synthesis after EAA ingestion is greater than that achieved by a mixed meal or an isocaloric serving of intact protein. Consistent with the acute findings, EAA supplementation can also ameliorate the loss of muscle mass and function during prolonged periods of strict bed rest in healthy individuals. These data hold promise that EAA supplementation may also have a potentially beneficial role in clinical populations.


   ACKNOWLEDGMENTS
 
Sincere thanks are extended to Drs. Arny Ferrando, Melinda Sheffield-Moore, and Robert Wolfe.


   FOOTNOTES
 
1 Manuscript received 25 April 2006. Back

2 Supported by grants from the NIH, NASA, the National Space Biological Research Institute (NSBRI) and the National Cattlemen's Beef Association (NCBA). Research at UTMB was conducted at the General Clinical Research Center (GCRC) and supported by grant M01 RR 00073 form the National Center for Research Resources. Back


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Summary
 LITERATURE CITED
 

1. Gore DC, Jahoor F, Wolfe RR, Herndon DN. Acute response of human muscle protein to catabolic hormones. Ann Surg. 1993;218:679–84.[Medline]

2. Woolf PD. Hormonal responses to trauma. Crit Care Med. 1992;20:216–26.[Medline]

3. Bessey PQ, Lowe KA. Early hormonal changes affect the catabolic responses to trauma. Ann Surg. 1993;218:476–91.[Medline]

4. Ferrando AA, Stuart CS, Sheffield-Moore M, Wolfe RR. Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J Clin Endocrinol Metab. 1999;84:3515–21.[Abstract/Free Full Text]

5. Wolfe RR. Metabolic response to burn injury: nutritional implications. Keio J Med. 1993;42:1–8.[Medline]

6. Woolf PD, McDonald JV, Feliciano DV, Kelly MM, Nichols D, Cox C. The catecholamine response to multisystem trauma. Arch Surg. 1992;127:899–903.[Abstract]

7. Brillon DJ, Zheng B, Campbell RG, Matthews DE. Effect of cortisol on energy expenditure and amino acid metabolism in humans. Am J Physiol. 1995;268:E501–13.

8. Ferrando AA, Lane HW, Stuart CA, Wolfe RR. Prolonged bed rest decreases skeletal muscle and whole-body protein synthesis. Am J Physiol. 1996;270:E627–33.

9. Ferrando AA, Wolfe RR. Effects of bed rest with or without stress. In: Kinney JM, Tucker HN, editors. Physiology, stress, and malnutrition: functional correlates, nutritional interventions. New York: Lippincott-Raven; 1997. p. 413–31.

10. Greenleaf JE, Kozlowski S. Physiological consequences of reduced physical activity during bed rest. Exerc Sport Sci Rev. 1982;10:84–119.[Medline]

11. Haruna Y, Suzuki Y, Kawakubo K, Yanagibori R, Gunji A. Decremental reset in metabolism during 20-days bed rest. Acta Physiol Scand Suppl. 1994;616:43–9.[Medline]

12. LeBlanc AD, Schneider VS, Evans HJ, Pientok C, Rowe R, Spector E. Regional changes in muscle mass following 17 weeks of bed rest. J Appl Physiol. 1992;73:2172–8.[Abstract/Free Full Text]

13. Stuart CA, Shangraw RE, Peters EJ, Wolfe RR. Effect of dietary protein on bed-rest-related changes in whole-body-protein synthesis. Am J Clin Nutr. 1990;52:509–14.[Abstract/Free Full Text]

14. Phillips SM, Parise G, Roy BD, Tipton KD, Wolfe RR, Tamopolsky MA. Resistance-training-induced adaptations in skeletal muscle protein turnover in the fed state. Can J Physiol Pharmacol. 2002;80:1045–53.[Medline]

15. Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR. Mixed muscle protein synthesis and breakdown following resistance exercise in humans. Am J Physiol. 1997;273:E99–107.

16. Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR. Exogenous amino acids stimulate net muscle protein synthesis in the elderly. J Clin Invest. 1998;101:2000–7.[Medline]

17. Volpi E, Mittendorfer B, Wolf SE, Wolfe RR. Oral amino acids stimulate muscle protein anabolism in the elderly despite higher first-pass splanchnic extraction. Am J Physiol. 1999;277:E513–20.

18. Paddon-Jones D, Sheffield-Moore M, Creson DL, Sanford AP, Wolf SE, Wolfe RR, Ferrando AA. Hypercortisolemia alters muscle protein anabolism following ingestion of essential amino acids. Am J Physiol Endocrinol Metab. 2003;284:E946–53.[Abstract/Free Full Text]

19. Paddon-Jones D, Sheffield-Moore M, Aarsland A, Wolfe RR, Ferrando AA. Exogenous amino acids stimulate human muscle anabolism without interfering with the response to mixed meal ingestion. Am J Physiol Endocrinol Metab. 2005;288:E761–767.[Abstract/Free Full Text]

20. Paddon-Jones D, Sheffield-Moore M, Katsanos CS, Zhang XJ, Wolfe RR. Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol. 2006;41:215–9.[Medline]

21. Paddon-Jones D, Sheffield-Moore M, Urban RJ, Sanford AP, Aarsland A, Wolfe RR, Ferrando AA. Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab. 2004;89:4351–8.[Abstract/Free Full Text]

22. Booth FW, Gordon SE, Carlson CJ, Hamilton MT. Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol. 2000;88:774–87.[Abstract/Free Full Text]

23. Wilkins CH, Birge SJ. Prevention of osteoporotic fractures in the elderly. Am J Med. 2005;118:1190–5.[Medline]

24. Akashi YJ, Springer J, Anker SD. Cachexia in chronic heart failure: prognostic implications and novel therapeutic approaches. Curr Heart Fail Rep. 2005;2:198–203.[Medline]

25. Azhar G, Wei JY. Nutrition and cardiac cachexia. Curr Opin Clin Nutr Metab Care. 2006;9:18–23.[Medline]

26. Evans W. Functional and metabolic consequences of sarcopenia. J Nutr. 1997;127:998S–1003S.

27. Dutta C, Hadley EC. The significance of sarcopenia in old age. J Gerontol A Biol Sci Med Sci. 1995; 50 Spec No: 1–4.

28. Roberts SB. Effects of aging on energy requirements and the control of food intake in men. J Gerontol A Biol Sci Med Sci. 1995; 50 Spec No: 101–106.

29. Bunker VW, Lawson MS, Stansfield MF, Clayton BE. Nitrogen balance studies in apparently healthy elderly people and those who are housebound. Br J Nutr. 1987;57:211–21.[Medline]

30. Fiatarone MA, O'Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330:1769–75.[Abstract/Free Full Text]

31. Fiatarone Singh MA, Bernstein MA, Ryan AD, O'Neill EF, Clements KM, Evans WJ. The effect of oral nutritional supplements on habitual dietary quality and quantity in frail elders. J Nutr Health Aging. 2000;4:5–12.[Medline]

32. Evans WJ. Effects of aging and exercise on nutrition needs of the elderly. Nutr Rev. 1996;54:S35–9.[Medline]

33. Pupovac J, Anderson GH. Dietary peptides induce satiety via cholecystokinin-A and peripheral opioid receptors in rats. J Nutr. 2002;132:2775–80.[Abstract/Free Full Text]

34. Darmaun D, Matthews DE, Bier DM. Physiological hypercortisolemia increases proteolysis, glutamine, and alanine production. Am J Physiol. 1988;255:E366–73.

35. Gelfand RA, Matthews DE, Bier DM, Sherwin RE. Role of counterregulatory hormones in the catabolic response to stress. J Clin Invest. 1984;74:2238–48.[Medline]




This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 Am. J. Clin. Nutr.Home page
D J. Millward, D. K Layman, D. Tome, and G. Schaafsma
Protein quality assessment: impact of expanding understanding of protein and amino acid needs for optimal health
Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1576S - 1581S.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Paddon-Jones, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paddon-Jones, D.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]