THE human aging process is accompanied by a significant

Transcription

1 Journal of Gerontology: MEDICAL SCIENCES 2007, Vol. 62A, No. 8, Copyright 2007 by The Gerontological Society of America Knee Strength Maintained Despite Loss of Lean Body Mass During Weight Loss in Older Obese Adults With Knee Osteoarthritis Xuewen Wang, 1 Gary D. Miller, 2 Stephen P. Messier, 2 and Barbara J. Nicklas 1 1 Section on Gerontology and Geriatric Medicine and 2 Department of Health and Exercise Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Background. The effects of weight loss on muscle function in older adults have not been well studied. This study determined the effects of a 6-month weight-loss intervention on muscle strength and quality in older obese adults with knee osteoarthritis. Methods. Participants were randomized to a weight loss (WL) (n¼44, years) or weight stable (WS) (n¼43, years) group. The WL intervention consisted of weekly educational meetings, a meal replacement diet, and a three-sessionper-week structured exercise program to achieve 10% 12% weight loss. The WS intervention included bimonthly group meetings and newsletters. Body composition and knee extensor strength were measured at baseline and after intervention. Results. The WL group decreased body weight, lean body mass, fat mass, and percent body fat (p,.001 for all). Concentric extension strength increased 25% in WL ( p..05), whereas eccentric extension decreased 6% in WS ( p ¼.028). Concentric muscle quality (strength per kg body weight or lean body mass) increased in WL ( p,.05), whereas eccentric muscle quality decreased in WS ( p,.05). Changes in lean body mass and fat mass were inversely associated with changes in most muscle strength and quality measures ( p,.05). Men and women did not differ in response to the intervention in knee strength outcomes. Conclusions. Hypocaloric dieting in combination with exercise training had beneficial effects on muscle strength/ quality, despite loss of lean body mass in this sample of older men and women. Greater fat loss was associated with greater gains in muscle strength and quality. More studies are needed regarding the mechanisms by which loss of fat mass increases muscle strength and quality. THE human aging process is accompanied by a significant decline in neuromuscular function and performance characterized by the inevitable reduction in skeletal muscle mass and strength (1). Studies have shown that isometric, concentric, and eccentric muscle strength declines with advancing age (2,3). Muscle quality (strength per unit of cross-sectional area or muscle mass) also declines with age (4,5). Moreover, the prevalence of joint dysfunction and arthritis, osteoarthritis in particular, increases progressively with age (6,7). All these factors contribute to the loss of functional mobility and independence present in many older adults. The global epidemic of obesity presents an increasing health concern. Among persons older than 60 years, 70.8% are overweight or obese, with 32.9% being obese (8). Excess body fat is a recognized risk factor for many chronic age-related diseases such as cardiovascular diseases and diabetes, and growing evidence from cross-sectional and longitudinal studies shows that obesity is associated with declines in physical function and greater onset of disability (9 13). Obesity is also associated with an increased risk of knee osteoarthritis (14,15), the leading cause of physical disability in older adults (16). Thus, being overweight or obese may exacerbate age-related loss of functional mobility and independence. Treatment of obesity via hypocaloric dieting has not been widely advocated in older adults because of concerns regarding potential adverse health consequences associated with weight loss. Unintentional weight loss is a common complication of some age-related diseases (17,18) and it not only decreases fat mass but also decreases lean body mass (muscle mass and bone mass), which could further impair physical function via potential loss of muscle strength and/ or quality (19,20). The effects of intentional weight loss on muscle strength or quality have not been well studied, especially in older persons. Some data show that weight loss from hypocaloric dieting combined with moderate physical activity increased muscle power, strength, quality, and physical performance in adults (21 25), but other data show weight loss by hypocaloric diet alone did not change muscle strength in young adults (26). Given the concerns related to weight loss in older persons, the purpose of this study was to determine the effects of a 6-month weight-loss intervention composed of caloric restriction and exercise training on muscle strength and quality in older obese adults with knee osteoarthritis. METHODS Study Design This study was a randomized clinical trial, the Physical Activity, Inflammation, and Body Composition Trial, designed to compare the effects of assignment to a 866

2 KNEE STRENGTH AND WEIGHT LOSS 867 Figure 1. Progress of participants through the study. weight-stable (WS) control group or to a weight loss (WL) group on measures of body composition and physical function in older adults with knee osteoarthritis. The primary results of the study, showing greater improvements in physical performance and self-reported physical function and pain (Western Ontario and McMaster University Osteoarthritis Index, WOMAC) in the WL than the WS group, are published elsewhere (27). It was approved by the Wake Forest University Institutional Review Board. We report here on the effects of the intervention on muscle strength and quality. Participants and Recruitment Participants were recruited over an 18-month period as previously described (27). The eligibility criteria included: 60 years of age; body mass index 30.0 and 45.0 kg/m 2 ; osteoarthritis in at least one knee; stable weight over the previous 3 months; sedentary without actively participating in 20 minutes of formal exercise 1 session per week or expending 200 calories per week in moderate- to highintensity activities within the past 6 months; and self-reported difficulty in at least one of the following activities attributed to knee pain: lifting or carrying groceries, walking one-quarter mile, getting in and out of a chair, or going up and down stairs. Individuals were excluded if they: (i) had an unstable medical condition or a condition where rapid weight loss or exercise was contraindicated, (ii) were unwilling to modify diet or physical activity patterns, or (iii) would not be able to comply with the intervention. Interventions Participants were randomly assigned to one of two groups (WS or WL) and were instructed to continue to take their medications. For participants in the WS group, weights were measured at bimonthly group meetings where pertinent health topics were discussed. They were encouraged to maintain their weight throughout the 6-month duration. Newsletters were sent in months 1, 3, and 5 describing facts on pertinent general health topics. Participants in the WL group underwent a 6-month weight-loss intervention to achieve a 10% 12% loss in initial body weight. Body weight was monitored at weekly behavioral and educational sessions. Diet was set based on providing a daily energy deficit of 1000 kcal, as determined by predicted energy expenditure, with a calorie distribution goal of ;20% from protein, ;25% from fat, and ;55% from carbohydrates. A maximum of two meal replacements (SlimFast shakes and bars) containing about 220 kcal with 7 10 g of protein, g of carbohydrates, g of fat, and 2 5 g of fiber were provided. For the third meal, a weekly menu plan with recipes was given for participants to follow. They also participated in a facility-based structured exercise program 3 days/week for 60 minutes consisting of aerobic and strength training. The primary mode of aerobic training was walking with 50% 85% of the agepredicted heart rate reserve. Strength training included leg extension, leg curl, heel raise, and step-ups using ankle cuff weights, weighted vest, and resistance training equipment. In addition, behavioral interventions including techniques to incorporate physical activity into daily life was emphasized on other days. Measurements Age and race were acquired by self-report. The outcome measures of this article, knee strength and body composition, were collected at baseline and 6-month visits. Knee concentric/eccentric extension muscle strength was assessed using a Kin-Com 125E isokinetic dynamometer (Chattanooga Group, Hixon, TN) at a velocity of 30 s 1 through a joint arc from 908 to 308 (08 ¼ full extension). The first and last 108 were subsequently deleted to account for acceleration and deceleration of the dynamometer at the ends of the range of motion and also to account for possible inconsistent effort. Two maximal reproducible trials were averaged, and the maximum number of each test was six with 30- to 60-second intervals. The tested leg was the one most affected by arthritis according to the participant. Weight and height were obtained (with shoes and outer garments removed) using a scale calibrated weekly. Percent body fat, lean body mass, fat mass, and total body mass were measured by dual-energy absorptiometry (DXA) (Delphi QDR; Hologic, Bedford, MA).

3 868 WANG ET AL. Statistical Analyses Statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, NC). Descriptive statistics were calculated, and values are reported as means 6 standard deviations (SD). We used factorial analysis of variance with a repeated measure on one factor, to compare mean body composition measures and knee strength outcomes across groups and before and after intervention. A Group 3 Time interaction was included in the model. Mean percent change was calculated as the average of individual differences before and after intervention. In the supplementary analysis, we also examined the main effect of gender and the interactions of Gender 3 Group, Gender 3 Time, and Gender 3 Group 3 Time. Pearson s correlations between changes in body composition and strength measurements were examined. An a level of 0.05 was selected. RESULTS Retention and Adherence Forty participants (90.9%) in WL and 33 (76.7%) in WS completed the study (Figure 1). The primary reasons for dropping out of the study were unhappiness with group assignment, inability to attend intervention due to personal reasons, poor health (unrelated to study outcomes), and moving from the area. Body composition and knee strength measurements were available from 73 and 64 participants, respectively, at both baseline and after intervention. Participants in the WL group attended an average of 77.5% of the exercise sessions and 75% of the nutrition sessions over the 6-month study duration. Demographics and Body Composition The WL and WS groups had similar mean age, percentage of women, and percentage of non-white participants (p..05 for all) (Table 1). Their baseline body weight, body mass index, lean body mass, fat mass, and percent body fat were also similar (p..05 for all), and interactions of Group 3 Time were significant (p,.001 for all). The intervention significantly decreased the above measurements in WL only (p,.001 for all). The total amount of weight loss in WL was composed of % fat and % lean mass. Muscle Strength and Quality For absolute concentric extension, the Group 3 Time interaction was significant (p ¼.02), with a 25% increase in WL only ( p..05) (Table 1). For absolute eccentric extension strength, the Group 3 Time interaction tended to be significant (p ¼.062). It decreased 5% in WS (p ¼.028), but increased 8% in WL (p..05). We also examined muscle quality expressed as knee strength relative to body weight and lean body mass. The Group 3 Time interactions for both concentric and eccentric extension strength per kilogram of body weight were significant ( p ¼.004 and.011, respectively) (Figure 2A and B). Concentric extension strength per kilogram of body weight increased from baseline to after intervention in WL ( p ¼.006), but remained unchanged in WS ( p..05). Table 1. Demographic Information, Body Composition, and Muscle Strength at Baseline and After a 6-Month Intervention for the Weight Loss (WL) and Weight Stable (WS) Groups Variable WL (N ¼ 40) WS (N ¼ 33) Age, y Female, % Non-White, % Weight, kg Baseline Postintervention * Change, % Body mass index, kg/m 2 Baseline Postintervention * Change, % Lean body mass, kg Baseline Postintervention * Change, % Fat mass, kg Baseline Postintervention * Change, % Percent body fat, % Baseline Postintervention * Change, % Concentric extension, Newton Baseline Postintervention Change, % Eccentric extension, Newton Baseline Postintervention y Change, % Concentric extension/body weight, Newton kg 1 Baseline Postintervention y Change, % Eccentric extension/body weight, Newton kg 1 Baseline Postintervention z y Change, % Concentric extension/lean mass, Newton kg 1 Baseline Postintervention y Change, % Eccentric extension/lean mass, Newton kg 1 Baseline Postintervention y Change, % Notes: All values are mean 6 standard deviation. Percent changes were calculated as the average of individual percent changes before and after intervention. Lean body mass, fat mass, and percent body fat, n ¼ 37 for WL and n ¼ 32 for WS; concentric extension, n ¼ 36 for WL and n ¼ 27 for WS; eccentric extension, n ¼ 34 for WL and n ¼ 28 for WS. *p,.001, y p,.05, z p ¼.072, compared to baseline.

4 KNEE STRENGTH AND WEIGHT LOSS 869 Table 2. Relationships Between Changes in Body Composition and Knee Extensor Strength in the Entire Sample Knee Extensor Strength Lean Mass Fat Mass Lean Mass* Fat Mass* Concentric extension y z y y Eccentric extension Concentric extension/body weight y y y y Eccentric extension/body weight z z z z Concentric extension/lean mass y y y y Eccentric extension/lean mass z z z Notes: All are Pearson s correlation coefficients. *Partial correlation coefficients after adjusting age, gender, and race. y p.01, z p.05, p ¼.09. Figure 2. A, Concentric extension knee strength per kilogram of body weight (Newton kg 1 ) at baseline and after a 6-month intervention by group. The Group 3 Time interaction was significant, p ¼.004. B, Eccentric extension knee strength per kilogram of body weight (Newton kg 1 ) at baseline and after a 6-month intervention by group. The Group 3 Time interaction was significant, p ¼.011. Eccentric extension strength per kilogram of body weight tended to increase in the WL group ( p ¼.072), but decreased in the WS group (p ¼.047). Similar results were obtained for knee strength per kilogram of lean body mass ( p ¼.013 and p ¼.023 for Group 3 Time interactions for concentric and eccentric extension strength, respectively). Concentric extension strength relative to lean body mass increased in WL only ( p ¼.030), whereas eccentric extension strength per kilogram of lean body mass decreased in the WS group only (p ¼.044). In addition, we examined whether there was a difference in response to the intervention between men and women by including the Gender 3 Time, Gender 3 Group, and Gender 3 Group 3 Time interactions. There were no statistically significant gender interactions ( p..05) for absolute and relative knee strength, indicating similar gender responses for all knee-strength outcomes. Body Composition and Muscle Strength and Quality Changes in lean mass and fat mass were related to changes in absolute concentric and all relative knee-strength outcomes (p,.05). Adjusting for age, gender, and race did not affect the correlations (Table 2). DISCUSSION This randomized, controlled trial demonstrated that weight loss via hypocaloric dieting in combination with moderate exercise training maintained absolute knee extensor muscle strength and improved muscle quality in older persons with osteoarthritis. These favorable effects occurred despite a significant loss of lean body mass during the 6- month intervention. We also found that greater fat loss was associated with greater gains in muscle strength and quality. Very few prior studies have reported the effects of a weight-loss intervention on muscle strength or quality in either younger or older persons. Our results are in line with those reported by Sartorio and colleagues (24), showing that a 3-week hypocaloric diet ( kcal/day) with lowintensity aerobic exercise in 18- to 77-year-old obese persons improved motor control and lower limb muscle power. Previous intervention studies have shown that resistance exercise training can significantly improve muscle strength even if increases in muscle mass are small (28,29). These results suggest that there are factors other than muscle mass contributing to gains in muscle strength, although muscle mass is important in determining muscle strength in elderly persons (30). Some observational data show an inverse association between adiposity and muscle strength and quality. In the Health, Aging and Body Composition Study (Health ABC), a cohort of well-functioning community-dwelling older persons aged years at baseline, body fat is an independent contributor to age-related declines in muscle strength and quality (leg and arm) (5). Sartorio and colleagues (23) have found improved isotonic strength after loss of fat mass in both men and women (mean age years). Moreover, a quadratic relationship was found between percent body fat and leg muscle quality, with individuals at the high and low extremes of percent body fat having lower levels of leg muscle quality than individuals in the midrange (5). Although the resistance training component of the exercise intervention in our study was modest, it may have had beneficial effects on muscle strength and quality, independent of weight loss. In addition, the loss of lean body mass may have been less than if a resistance training component was not incorporated into the intervention. However, as our data show that the magnitude of the changes in strength and quality were related to the loss of body fat, there are likely

5 870 WANG ET AL. mechanisms by which loss of adipose tissue may also improve muscle strength and quality. Biologically, fat may contribute to the regulation of protein metabolism and ultimately to accumulation of lean mass (31,32). In addition, there were no relationships between changes in pain (measured by the Western Ontario and McMaster University Osteoarthritis Index) and changes in knee strength (data not shown), suggesting that improvement in knee pain did not contribute to the maintenance/improvement in knee strength in our study. Another mechanism may be through loss of intramyocellular triglyceride with weight loss. Observational data show that a lower muscle density, that is, higher muscle lipid content, assessed by an x-ray attenuation on computed tomography scan, is associated with lower voluntary isokinetic knee extensor strength independent of subcutaneous and midthigh adiposity (33). Prior studies have also shown that weight loss reduces muscle lipid content (34,35). In addition, as weight loss reduces biomarkers of inflammation (36), and there is a link between inflammation and muscle mass and strength (37 39), a loss of adipose tissue may benefit muscle strength through a reduction in inflammation. Therefore, the reduction in intramyocellular triglyceride and inflammation may be potential mechanisms by which muscle strength and quality improved with weight loss. Gender differences in muscle strength and quality with aging have been found (3); however, very few studies examined whether there are gender difference in the effects of diet and exercise-training intervention on muscle strength and quality. One study showed that a 3-week hypocaloric diet and aerobic and strength training in younger adults improved absolute maximum leg power output in women but not in men (23). However, improvements in leg power relative to body weight or fat-free mass, and total isotonic strength, were similar between men and women. Our study found that responses to the intervention were not different between genders for absolute or relative knee extensor strength. As is the case with most randomized trials, more participants in the treatment group completed the intervention compared to the control group. However, we chose not to perform an intent-to-treat analysis because our primary purpose was to assess whether actual amount of weight loss affected muscle strength. Although we found that greater fat loss was associated with greater gains in muscle strength and quality, we were not able to determine if this was a causal relationship. In addition, the intervention for the WL group included caloric restriction and a structured exercise program; therefore, we were not able to examine their individual effect on the outcome variables. Conclusion Results from this randomized, controlled trial in older persons show that intentional weight loss via hypocaloric dieting and exercise training improved knee extensor strength and quality despite loss of lean body mass. Thus, it may be appropriate to prescribe weight loss in older obese persons, particularly those with osteoarthritis. However, additional studies examining the effects of intentional weight loss on other measures of physical function, and especially on onset of physical disability, are needed. Moreover, more research is needed regarding the mechanisms by which loss of fat mass increases muscle strength and quality. ACKNOWLEDGMENTS This work was supported by the SlimFast Nutrition Institute, Wake Forest University, the Claude D. Pepper Older American Independence Center (National Institutes of Health [NIH] Grant P30 AG21332), and the Wake Forest University General Clinical Research Center (NIH Grant M01-RR07122). We thank Pamela Moser for her work with the intervention and Gretchen Austin, Tina Ellis, Shannon Brown, Kristen Klingler, and Meghan Provonost for the data collection. CORRESPONDENCE Address correspondence to Xuewen Wang, PhD, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC xwang@ wfubmc.edu REFERENCES 1. Doherty TJ. Aging and sarcopenia. J Appl Physiol. 2003;95: Hurley BF. Age, gender, and muscular strength. J Gerontol Biol Sci Med Sci. 1995;50A: Lindle RS, Metter EJ, Lynch NA, et al. Age and gender comparisons of muscle strength in 654 women and men aged yr. J Appl Physiol. 1997;8: Lynch NA, Metter EJ, Lindle RS, et al. Muscle quality. I. Ageassociated differences between arm and leg muscle groups. J Appl Physiol. 1999;86: Newman AB, Haggerty CL, Goodpaster B, et al. Strength and muscle quality in a well-functioning cohort of older adults: the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2003;51: Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum. 1987;30: Doherty M. Risk factors for progression of knee osteoarthritis. Lancet. 2001;358: Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, JAMA. 2004;291: Apovian CM, Frey CM, Wood GC, Rogers JZ, Still CD, Jensen GL. Body mass index and physical function in older women. Obes Res. 2002;10: Broadwin J, Goodman-Gruen D, Slymen D. Ability of fat and fat-free mass percentages to predict functional disability in older men and women. J Am Geriatr Soc. 2001;49: Zoico E, Di Francesco V, Guralnik JM, et al. Physical disability and muscular strength in relation to obesity and different body composition indexes in a sample of healthy elderly women. Int J Obes Relat Metab Disord. 2004;28: Jensen GL, Friedmann JM. Obesity is associated with functional decline in community-dwelling rural older persons. J Am Geriatr Soc. 2002;50: Bannerman E, Miller MD, Daniels LA, et al. Anthropometric indices predict physical function and mobility in older Australians: the Australian Longitudinal Study of Ageing. Public Health Nutr. 2002;5: Holmberg S, Thelin A, Thelin N. Knee osteoarthritis and body mass index: a population-based case-control study. Scand J Rheumatol. 2005;34: Coggon D, Reading I, Croft P, McLaren M, Barrett D, Cooper C. Knee osteoarthritis and obesity. Int J Obes Relat Metab Disord. 2001;25: Sharma L, Kapoor D, Issa S. Epidemiology of osteoarthritis: an update. Curr Opin Rheumatol. 2006;18:

6 KNEE STRENGTH AND WEIGHT LOSS French SA, Folsom AR, Jeffery RW, Williamson DF. Prospective study of intentionality of weight loss and mortality in older women: the Iowa Women s Health Study. Am J Epidemiol. 1999;149: Wannamethee SG, Shaper AG, Whincup PH, Walker M. Characteristics of older men who lose weight intentionally or unintentionally. Am J Epidemiol. 2000;151: Villareal DT, Apovian CM, Kushner RF, Klein S. Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am J Clin Nutr. 2005;82: Lee JS, Kritchevsky SB, Tylavsky F, et al. Weight change, weight change intention, and the incidence of mobility limitation in wellfunctioning community-dwelling older adults. J Gerontol Biol Sci Med Sci. 2005;60A: Lafortuna CL, Resnik M, Galvani C, Sartorio A. Effects of non-specific vs individualized exercise training protocols on aerobic, anaerobic and strength performance in severely obese subjects during a short-term body mass reduction program. J Endocrinol Invest. 2003;26: Sartorio A, Lafortuna CL, Agosti F, Proietti M, Maffiuletti NA. Elderly obese women display the greatest improvement in stair climbing performance after a 3-week body mass reduction program. Int J Obes Relat Metab Disord. 2004;28: Sartorio A, Maffiuletti NA, Agosti F, Lafortuna CL. Gender-related changes in body composition, muscle strength and power output after a short-term multidisciplinary weight loss intervention in morbid obesity. J Endocrinol Invest. 2005;28: Sartorio A, Lafortuna CL, Conte G, Faglia G, Narici MV. Changes in motor control and muscle performance after a short-term body mass reduction program in obese subjects. J Endocrinol Invest. 2001;24: Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004;50: Zachwieja JJ, Ezell DM, Cline AD, et al. Short-term dietary energy restriction reduces lean body mass but not performance in physically active men and women. Int J Sports Med. 2001;22: Miller GD, Nicklas BJ, Davis C, Loeser RF, Lenchik L, Messier SP. Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis. Obesity. 2006;14: Tracy BL, Ivey FM, Hurlbut D, et al. Muscle quality. II. Effects of strength training in 65- to 75-yr-old men and women. J Appl Physiol. 1999;86: Fiatarone MA, O Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330: Reed RL, Pearlmutter L, Yochum K, Meredith KE, Mooradian AD. The relationship between muscle mass and muscle strength in the elderly. J Am Geriatr Soc. 1991;39: Welle S, Statt M, Barnard R, Amatruda J. Differential effect of insulin on whole-body proteolysis and glucose metabolism in normal-weight, obese, and reduced-obese women. Metabolism. 1994;43: Bruce AC, McNurlan MA, McHardy KC, et al. Nutrient oxidation patterns and protein metabolism in lean and obese subjects. Int J Obes. 1990;14: Goodpaster BH, Carlson CL, Visser M, et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC Study. J Appl Physiol. 2001;90: Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes. 1999;48: Houmard JA, Tanner CJ, Yu C, et al. Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-coas in morbidly obese subjects. Diabetes. 2002;51: Nicklas BJ, You T, Pahor M. Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training. CMAJ. 2005;172: Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol Med Sci. 2002;57A:M326 M Charters Y, Grimble RF. Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats. Biochem J. 1989;258: Goodman MN. Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med. 1994;205: Received May 28, 2006 Accepted November 10, 2006 Decision Editor: Luigi Ferrucci, MD, PhD