“Muscle – not just for athletes!” Muscle mass, disability & quality of life. Dr. Andrew Lemmey School of Sport, Health and Exercise Sciences Bangor University, UK Determinants of Muscle Atrophy: Loss of Muscle Fibers → Reduction of Muscle Fibers Size → Pathophysiology of muscle loss secondary to aging Tomlinson and Irving (1977) Lexell et al. (1988) Cachexia / sarcopenia is associated with poor outcome Consequences of Sarcopenia: Mortality (Kotler et al., 1989) Muscle Atrophy and Mortality Kato et al. (2003) Muscle Atrophy at Admission and Length of Stay in Hospital High FFMI Low FFMI Normal FFMI Pichard et al. (2004) Consequences of Sarcopenia: Disability (Baumgartner, 2000) Muscle Mass and Strength in RA 60 30 50 40 20 30 10 SST-30, reps 20 group allocation 10 group allocation healthy 0 RA 2000 4000 6000 8000 10000 arms lean mass, g healthy 0 RA 12 14 16 18 20 22 24 26 28 relative legs lean mass, % Healthy r = 0.94, p < 0.001 Healthy r = 0.59, p < 0.01 RA r = 0.73, p < 0.001 RA r = 0.40, p = 0.07 KES (N) 60 r = 0.832 40 Controls Patients 20 0 0 10 20 30 Leg lean mass (kg) Fig. 3. Bivariate linear regression analysis between body composition data and measures of functional capacity. KES, Knee extensor strength. Analysis is based on pooled data for patients and controls. r, Pearson correlation coefficient. *, p < 0.005. 30sec SST 25 20 15 10 5 0 Controls Patients r = 0.615 0 5 10 15 AMMI (kg/m2) Fig. 2. Bivariate linear regression analysis between body composition data and measures of functional capacity. 30sec SST, 30 second sit to stand chair test. Analysis is based on pooled data for patients and controls. r, Pearson correlation coefficient. *, p < 0.005. • The identification of effective means of treating sarcopenia/cachexia (muscle wasting) is very important since increasing muscle mass in individuals with muscle wasting has the potential to decrease disability and morbidity, increase life expectancy, and improve quality of life in these patients Muscle Loss (rate x duration) Aging Disuse Drugs Malnutrition Disease → Sarcopenia Muscle Loss Secondary to Disuse (SHUTTLE and MIR missions of 16-28 weeks duration) Preflight Postflight Δ Δ% P BMC (kg) 2.95 2.85 -0.10 -3.4 <0.01 Fat (kg) 15.04 15.54 +0.50 +3.3 NS LBM (kg) 59.42 57.32 -2.10 -3.5 <0.001 Total (kg) 77.42 75.11 -1.71 -2.2 <0.02 Le Blanc et al. (2000) Muscle Loss Secondary to Systemic Disease RA PATIENTS HEALTHY CONTROLS Δ Δ% P 12:8 12:8 NA NA NA Age (yrs) 54 ± 11 54 ± 11 0 0 1.00 Height (cm) 166 ± 8 169 ± 11 -3 2 0.36 Body Mass (kg) 78.6 ± 12.7 78.4 ± 11.0 0.2 0 0.95 BMI (kg/m2) 28.5 ± 3.6 27.6 ± 3.9 0.9 3 0.46 Muscle Mass (kg) 19.6 ± 5.4 22.1 ± 7.1 -2.5 -11 0.01 % Body Fat 39.8 ± 8.8 35.4 ± 11.6 4.4 12 0.05 Sex (Female:Male) Marcora et al., Journal of Rheumatology (2005) 32(6):1031-1039 Standard medical treatment does not completely prevent cachexia Muscle Loss Secondary to Drug Therapy (Androgen Deprivation Therapy in Prostate Cancer Patients) Baseline 1 Month 3 Months P Testosterone (nmol/l) 14.5 ± 4.1 0.9 ± 0.4 1.2 ± 1.0 < 0.0001 Fat Mass (kg) 20.2 ± 9.4 22.5 ± 10.5 21.9 ± 9.6 < 0.01 LBM (kg) 63.2 ± 6.8 62.3 ± 5.4 61.5 ± 6.0 < 0.05 83 ± 14 85 ± 14 83 ± 14 NS Body Mass (kg) Smith et al. (2001) Muscle Protein Metabolism in Health and Disease 12.5 10 7.5 5 Anabolism Catabolism Net 2.5 0 -2.5 -5 -7.5 Young PRT Old Acute Chronic Standard drug therapy, including anti-TNF therapy, neither completely prevents muscle wasting, nor restores muscle mass Consequently, there is a need for anabolic therapy in treating patients with cachexia Anabolic Therapies Progressive resistance training (PRT) Dietary supplements Anabolic hormones Progressive Resistance Training Can progressive resistance training reverse rheumatoid cachexia? A Phase II Trial RA Patients (n = 20) Healthy Controls (n = 20) Δ P 54 ± 11 54 ± 11 NA NA 12:8 12:8 NA NA Disease Duration, yrs 8.1 ± 5.4 NA NA NA RADAI, 0-10 2.6 ± 1.5 NA NA NA Height, cm 166 ± 8 169 ± 11 -2% 0.36 Body Mass, kg 78.6 ± 12.7 78.4 ± 11.0 0% 0.95 BMI, kg/m2 28.5 ± 3.6 27.6 ± 3.9 1% 0.37 Arms Lean Mass, kg 4.3 ± 1.6 4.8 ± 2.0 -11% 0.02 Legs Lean Mass, kg 13.1 ± 3.2 14.7 ± 4.3 -11% 0.01 Trunk Lean Mass, kg 23.3 ± 4.6 24.1 ± 4.9 -3% 0.46 % Body Fat 39.8 ± 8.8 35.4 ± 11.6 12% 0.05 Characteristic Age, yrs Sex (Female:Male) Marcora et al. Journal of Rheumatology (2005) 32(6):1031-1039 Intense Progressive Resistance Training Very Intense!!! Exercise Dose Variable Rall et al. Marcora et al. Muscle action Dynamic Dynamic 1-2 s concentric and eccentric 1-2 s concentric and eccentric 8 8 80% of 1-RM 80% of 1-RM 3 3 1-2 min 1-2 min Number of exercises per training session 5 8 Training frequency 2 3 Total number of lifts per week 240 576 12 weeks 12 weeks Velocity Reps per set Load Sets per exercise Rest periods Duration Training Progression Average training session load, kg 10000 9500 9000 * 8500 8000 7500 7000 6500 6000 1 2 3 4 5 6 7 8 Week of training * P < 0.01 9 10 11 12 Results: Body Composition Difference in grams 1500 1242 1000 500 839 280 P = 0.08 0 P < 0.01 P < 0.01 P < 0.01 Total LM Arms LM Legs LM -500 -1000 -752 Trunk FM FM = Fat Mass; LM = Lean Mass. Significance was tested by ANCOVA on follow-up scores using baseline scores as covariate. Objective Functional Capacity Tests Rickli & Jones, Senior Fitness Test Manual, Human Kinetics (2001) 30sec sit-stand test (lower body strength) Leg extension (lower body strength) Dumbbell arm curls (30sec) (upper body strength) Hand grip strength (upper body strength) 8’ up-and-go (agility/dynamic balance) 6 min walk (aerobic endurance) 2-min step test (aerobic endurance) Chair sit-and-reach (lower body flexibility) Rickli & Jones, Senior Fitness Test Manual, Human Kinetics (2001) Results: Muscle Strength 40 Percent Difference 35 30 P = 0.04 P < 0.01 P < 0.01 25 20 P = 0.07 15 10 5 0 Hand-Grip Elbow Flexors Knee Extensors Chair Test Significance was tested by ANCOVA on follow-up scores using baseline scores as covariate. Significant decrease (-0.25 HAQ score) in disability (P = 0.01) by ANCOVA .2 0.0 -.2 D advanced ADLs -.4 group allocation -.6 control group training group -.8 Total Population -1000 0 1000 D leg lean r = -0.50, P = 0.03 2000 Can 24 wks progressive resistance training reverse cachexia in rheumatoid arthritis patients? A RCT Characteristic PRT group (n=13) ROM controls (n=15) p Age (yrs) 55.6 ± 8.3 60.6 ± 11.2 0.201 Gender (F/M) 11/2 12/3 0.686 Disease duration (yrs) 6.2 ± 6.3 10.4 ± 9.4 0.146 Disease activity score (DAS) 3.29 ± 1.27 3.28 ± 1.07 0.989 Postmenopausal 9 9 HRT 1 0 Lemmey et al., Arthritis & Rheum (2009) 61:1726-34 Exercise Dose Variable Lemmey et al. (2009) Marcora et al. (2005) Dynamic Dynamic 1-2 s concentric and eccentric 1-2 s concentric and eccentric 8 8 80% of 1-RM 80% of 1-RM 3 3 1-2 min 1-2 min Number of exercises per training session 8 8 Training frequency 2 3 Total number of lifts per week 384 576 24 weeks 12 weeks Muscle action Velocity Reps per set Load Sets per exercise Rest periods Duration Effects of 24 wks high intensity PRT on body composition in RA patients PRT group (n=13) ROM controls (n=15) p ή Lean body mass (kg) pre post 37.3 ± 4.0 38.8 ± 4.2 40.4 ± 8.9 40.0 ± 8.7 0.006 0.26 Appendicular lean mass (kg) pre post 14.3 ± 1.8 15.5 ± 2.2 15.7 ± 4.1 15.5 ± 4.0 0.002 0.33 Total body protein (kg) pre post 6.40 ± 2.02 8.20 ± 1.84 7.66 ± 3.56 7.25 ± 3.93 0.004 0.28 Total fat mass (kg) pre post 27.8 ± 12.0 25.5 ± 10.8 31.3 ± 8.7 29.9 ± 10.4 0.657 Trunk fat mass (kg) pre post 14.0 ± 6.5 11.5 ± 5.2 16.1 ± 5.7 14.8 ± 6.1 0.489 Variable Effects of 24 wks high intensity PRT on body composition in RA patients Variable PRT group (n=13) ROM controls (n=15) Cachectic pre Post 9 4 7 7 Obese pre post 10 7 12 12 Cachectic-obese pre post 5 2 5 5 Lemmey et al., Arthritis & Rheum (2009) 61:1726-34 Effects of 24 wks high intensity PRT on physical function in RA patients 30 Arm Curls (reps) 25 Pre * Post 20 15 10 5 B 30s sit-to-stand (reps) A 18 15 12 9 6 3 0 0 PRT PRT Cont C D 12 9 Knee extensor strength (N) 15 50 ft walk (s) *** 21 * 6 3 0 PRT Cont ** 500 400 300 200 100 0 Cont PRT * p<0.05, ** p<0.01, *** p<0.001 (group x time interaction). “healthy control” values (gender and age weighted) Cont Line represents Values are the mean ± SD. P values are for group x time interaction. Effect size was calculated as eta squared (η2), with thresholds for small, moderate, large and very large effects set at .01, .08, .26 and .50 respectively. Muscle IGF values (mIGF) are for PRT group (n=9) and control group (n=5), whilst serum IGF (sIGF) values are for PRT group (n=13) and control group (n=15). Lemmey et al., Arthritis & Rheum (2009) 61:1726-34 pg/μg 16 14 12 10 8 6 4 2 0 Controls Patients ** ** IGF-І IGFBP-3 Fig. 3. Skeletal muscle IGF-І and IGFBP-3 levels (normalized for total protein content) for 5 healthy controls and 7 HD patients. Values are mean ± SD. **, p < 0.001 from healthy controls. Macdonald et al., Clin Physiol Functional Imaging (2005) 25:113-18 Pharmacological Nutrition Nutritional Treatment of Rheumatoid Cachexia Number of nutrition intervention trials [either randomized controlled trials (RCTs) or observational trials (OTs)] in patients with chronic diseases (Akner and Cederholm, 2001) Randomised Controlled Trial of Juven in RA Patients What is Juven? Oral mixture of amino acids: Arginine = 14 g/day Glutamine = 14 g/day β-hydroxy-β-methylbutyrate (HMB) = 3 g/day Marcora et al., Clinical Nutrition (2005) 24(3): 442-454 Randomised Controlled Trial of Juven in RA Patients • 40 RA patients were randomly assigned to either Juven (n = 20) or “Placebo” (n = 20) • Placebo = a nitrogen and calorie balanced mix of 11 g of alanine, 1.75 g of glutamic acid, 6.10 g of glycine, and 4.22 g of serine • Both subjects and researchers were unaware of allocation until analysis (double blind) • Subjects were tested at baseline and after 12 weeks of oral supplementation • 36 subjects completed the study Changes in Appendicular Muscle Mass 600 (Main Factor Time P < 0.05) 500 grams 400 300 200 100 0 Juven Data presented as Mean ± SEM Placebo Randomised Controlled Trial of Juven in RA Patients HMB/Arg/Glut Placebo 11.0 10.5 Total body protein, kg 10.0 ¶ 9.5 # 9.0 8.5 8.0 7.5 7.0 Pretest Posttest Non significant group x time interaction; P = 0.74, η2 = 0.00 # Significant main effect for time; P = 0.02, η2 = 0.16 Changes in Lower Body Function 16 Juven Sit-to-stand reps in 30" (Main Factor Time P < 0.05) Placebo 15 14 13 12 11 10 Pre Post Data presented as Mean ± SEM Anabolic Hormones Anabolic/Androgenic Steroids Age group 50–59 yr RA Healthy P n 34 23 NA Age (yr) 55.5 55.1 NS T (nmol/l) 14.9 (5.1) 18.6 (6.0) <0.01 SHBG (nmol/l) 32.9 (13.2) 34.7 (12.9) NS T/SHBG 0.49 (0.2) 0.56 (0.2) <0.05 NST (nmol/l) 8.9 (2.5) 11.4 (3.0) <0.01 Percentage hypogonadal 35 9 <0.05 Tengstrand et al. (2002) Anabolic Steroids in RA: Women (Bird et al., 1987) • Single-blind, randomised, parallel, controlled trial • 24 female RA patients received 50 mg of nandrolone decanoate every third week for 2 years • 23 female RA patients received only standard medical treatment • Patients assessed at month 0, 6, 12, 18, 24 • Body composition by neutron activation analysis and whole-body counting • Main focus osteoporosis, no effect • No effect on disease activity • Striking improvement in anemia • Side effects were hoarseness, slight facial hair growth and occasionally breast enlargement TBN (g) Anabolic Steroids in RA: Women (Bird et al., 1987) 1250 1200 1150 1100 1050 1000 950 900 850 800 * Nandrolone Control 0 6 12 18 24 Month * P < 0.01 Equivalent to 3 kg of FFM. Body mass did not change Johansen et al., JAMA, 1999 5 * 4 Change (kg) 3 2 Placebo 1 Nandrolone Decanoate 0 -1 -2 -3 * -4 Lean mass Fat mass 6 months 6 months Nandrolone decanoate: a dose response curve in patients with end stage renal disease • Aims: • 1) to determine the most efficacious dose of ND for reversing muscle loss and improving physical function in ESRD patients • 2) to assess the role of ND in reducing osteodystrophy, anaemia and CV risk, and improving psychological parameters and QoL • Macdonald et al., Nephron Clinical Practice (2007) 106:125-135 • Randomised, double-blind study • 60 HD or PD patients (Bangor, Clan Clwyd, Wrexham Renal units) • Doses: low (males = 50mg/wk; females = 25mg/wk) medium (males = 100mg/wk; females = 50mg/wk) high (males = 200mg/wk; females = 100mg/wk) i.m. injection weekly for 6 mths • Measures: • Body composition (DXA, BIS), * BMD at neck of femur, lumbar spine (L2-L4) • Physical function (30 sec SST, arm curl, 8’ up + go, 6 min walk) • Macdonald et al., Nephron Clinical Practice (2007) 106:125-135 • Measures (cont.) • Anaemia: Hb, Hct • Psychological: QoL (SF-36), fatigue (Bidimensional Fatigue Scale), aggression (Aggression Questionnaire), anxiety and depression (HADS), body image (BodyImage Ideals Questionnaire) • Safety: LFT’s, blood lipids, baseline sex hormone profile, PSA. Other possible side effects e.g. masculinisation, hirsutism, oedema, acne etc. - continuously monitored • Study supported by N. Wales Central Research Ethics Committee and N. Wales Health and Social Care R&D Collaboration • Macdonald et al., Nephron Clinical Practice (2007) 106:125-135 Dose response of nandrolone on muscle mass ALM change score (%) 12 * 10 # 8 6 4 2 0 -2 -4 0 50 100 200 Dose (mg/week) ALM, appendicular lean mass; *, p < 0.01 vs.. control; #, p < 0.01 vs.. low dose group. Macdonald et al., Nephron Clinical Practice (2007) 106:125-135 Nandrolone decanoate as adjunct therapy in patients with rheumatoid arthritis • Study conducted by Dr. Rao Elamanchi • Randomised, double-blind, placebo controlled • 40 stable male RA patients (receiving either 100mg/wk ND or placebo by fortnightly i.m. injection for 6 mths) • In addition to measures of renal ND study, disease activity (EULAR criteria e.g. no. of swollen/tender jts, ESR, CRP) will be assessed Summary and Conclusions i • Muscle loss is a common consequence of ageing and RA (as it is of most chronic diseases), and a major factor in disability, and thus needs to be monitored (i.e. body composition assessment) • Even successful pharmaceutical control of disease does not restore lost muscle mass • Need for anabolic therapy in subjects with cachexia / sarcopenia Summary and Conclusions ii • HI PRT is effective in reversing muscle wasting and restoring function in the aged, RA patients, and patients with other chronic diseases • Objective physical function tests are valuable means of evaluating physical capacity and disability, and also provide an indication of muscle mass • Drs. Andrew Lemmey, Sam Marcora, Jeanette Thom, Jamie Macdonald; SSHES • Prof. Peter Maddison, Dr. Jerry Jones, Rheumatology Dept., Ysbyty Gwynedd; SSHES • Drs. Verena Matschke, Tosan Okoro, Naushad Jungalee, Ysbyty Gwynedd • Dr. Mardi Jibani, Renal Unit, Ysbyty Gwynedd; Dr. Mick Kumwenda, Renal Unit, Ysbyty Glan Clywd • PhD students: Sam Marcora, Jamie Macdonald, Francesco Casanova, Sally Wilson; MPhil student: Kath Chester, plus MSc and intercollated degree students (i.e. medical students) • Prof. Nick Stuart, Oncology, Ysbyty Gwynedd • Mr. Glynne Andrews, Orthopaedic Dept., Ysbyty Gwynedd • Prof. Jeff Holly, Division of Surgery, University of Bristol • Prof. Claire Stewart, Dept. of Exercise and Sport Science, MMU Dual-Energy X-Ray Absorptiometry Bioelectrical Impedance Analysis • BIA is based on the conductive and non-conductive properties of various biological tissues • Most of the body's FFM is composed of conductive tissues such as muscle, while fat is part of the non-conductive tissue mass • The volume of these tissues can be estimated from the impedance (Z) to an applied electric current (typically, 800μA at a fixed frequency, usually 50kHz) flowing through the body • COST - single frequency BIA: £400-2k; multifrequBIA: >£3k Bioelectrical Impedance Analysis (ii) • Prediction equations use impedance to estimate TBW • LBM then calculated from an assumed hydration of lean tissue (73.2%). FM = BM – est. LBM • Typical SEE for TBW = 3-10%; CV for RM = 1-3%. Assuming correct procedures are observed • Kyle et al., “Body composition measurements: interpretation finally made easy for clinical use” Curr Opin Clin Nutr Metab Care. 2003; 6(4): 387-93 Rheumatoid Arthritis • Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis primarily affecting small joints of hands and feet • Prevalence = 1% (women:men = 3:1) • Despite aggressive treatments – 80% of RA patients disabled after 20 years (Scott et al, 1987) – 7x’s greater risk of disability (Sokka et al, 2002) – Work disability after 10 years = 44% (Sokka et al, 1999) • 41% variability in disability in RA unaccounted for (Escalante and Del Rincon, 2002) • In RA – 13% lower body cell mass (BCM) (Roubenoff et al, 1994) – Strong dose relationship between BCM and disease severity (Roubenoff et al, 1994) – Lean body mass (LBM) = 10-15% lower (Rall et al, 1996) • Relative muscle mass is a reliable indicator of functional limitation and disability in an ageing population (Jansen, 2002) Rheumatoid Cachexia • Rheumatoid cachexia is defined as:– ‘An involuntary loss of BCM that predominates in skeletal muscle mass and occurs with no or little weight loss in presence of stable or increasing fat mass’ – (Walsmith and Roubenoff, 2002) • Affects 2/3 RA patients and thought to play important role in disease pathogenesis (Walsmith and Roubenoff, 2002) Low activity (low levels and/or resistance) of other anabolic hormones Usually normal appetite and protein-energy intake Therapy with corticosteroids Modified from Walsmith and Roubenoff (2002)