Transcript P - Bangor University

“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)