“Muscle – not just for athletes!” Muscle mass, disability & quality

of life.

Dr. Andrew LemmeySchool 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

Lexell et al. (1988)

Tomlinson and Irving (1977)

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

Pichard et al. (2004)

Low

FFM

I

Norm

al FFM

IH

igh

FFMI

Consequences of Sarcopenia: Disability(Baumgartner, 2000)

Muscle Mass and Strength in RA

arms lean mass, g

100008000600040002000

gri

p s

tre

ng

th,

kg

60

50

40

30

20

10

0

group allocation

healthy

RA

relative legs lean mass, %

282624222018161412

SS

T-3

0,

rep

s

30

20

10

0

group allocation

healthy

RA

Healthy r = 0.94, p < 0.001

RA r = 0.73, p < 0.001

Healthy r = 0.59, p < 0.01

RA r = 0.40, p = 0.07

0

20

40

60

0 10 20 30

Leg lean mass (kg)

KE

S (

N)

Controls

Patients

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.

r = 0.832

0

510

1520

25

0 5 10 15

AMMI (kg/m2)

30se

c SS

T Controls

Patients

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.

r = 0.615

• 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

Peak Muscle Mass

GeneticMakeup

Nutrition

PhysicalActivity

Gender

Sarcopenia→

Muscle Loss Secondary to Disuse(SHUTTLE and MIR missions of 16-28 weeks duration)

Le Blanc et al. (2000)

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

Muscle Loss Secondary to Systemic Disease

RA PATIENTS

HEALTHY CONTROLS

Δ Δ% P

Sex (Female:Male)

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

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)

Smith et al. (2001)

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

Body Mass (kg) 83 ± 14 85 ± 14 83 ± 14 NS

Muscle Protein Metabolism inHealth and Disease

-7.5

-5

-2.5

0

2.5

5

7.5

10

12.5

Young PRT Old Acute Chronic

AnabolismCatabolismNet

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

Characteristic RA Patients(n = 20)

Healthy Controls(n = 20) Δ P

Age, yrs 54 ± 11 54 ± 11 NA NA

Sex (Female:Male) 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

Marcora et al. Journal of Rheumatology (2005) 32(6):1031-1039

Intense Progressive Resistance Training

Very Intense!!!

Exercise DoseVariable Rall et al. Marcora et al.

Muscle action Dynamic Dynamic

Velocity1-2 s concentric and

eccentric1-2 s concentric and

eccentric

Reps per set 8 8

Load 80% of 1-RM 80% of 1-RM

Sets per exercise 3 3

Rest periods 1-2 min 1-2 min

Number of exercisesper training session

5 8

Training frequency 2 3

Total number of lifts per week

240 576

Duration 12 weeks 12 weeks

Training Progression

6000

6500

7000

7500

8000

8500

9000

9500

10000

1 2 3 4 5 6 7 8 9 10 11 12

Week of training

Ave

rag

e tr

ain

ing

se

ssio

n lo

ad

, kg

*

* P < 0.01

Results: Body Composition

-752

1242

280

839

-1000

-500

0

500

1000

1500

Trunk FM Total LM Arms LM Legs LM

Dif

fere

nce

in g

ram

s

P = 0.08

P < 0.01 P < 0.01 P < 0.01

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

Significance was tested by ANCOVA on follow-up scores using baseline scores as covariate.

0

5

10

15

20

25

30

35

40

Hand-Grip Elbow Flexors KneeExtensors

Chair Test

Pe

rce

nt

Dif

fere

nce

P = 0.04 P < 0.01

P = 0.07

P < 0.01

Significant decrease (-0.25 HAQ score) in disability (P = 0.01) by ANCOVA

r = -0.50, P = 0.03

D leg lean

200010000-1000

D a

dva

nce

d A

DL

s

.2

0.0

-.2

-.4

-.6

-.8

group allocation

control group

training group

Total Population

Can 24 wks progressive resistance training reverse cachexia in rheumatoid arthritis patients?

A RCT

CharacteristicPRT 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 DoseVariable Lemmey et al. (2009) Marcora et al. (2005)

Muscle action Dynamic Dynamic

Velocity1-2 s concentric and

eccentric1-2 s concentric and

eccentric

Reps per set 8 8

Load 80% of 1-RM 80% of 1-RM

Sets per exercise 3 3

Rest periods 1-2 min 1-2 min

Number of exercisesper training session

8 8

Training frequency 2 3

Total number of lifts per week

384 576

Duration 24 weeks 12 weeks

Effects of 24 wks high intensity PRT on body composition in RA patients

Variable PRT group(n=13)

ROM controls(n=15)

p ή

Lean body mass (kg)prepost

37.3 ± 4.038.8 ± 4.2

40.4 ± 8.940.0 ± 8.7

0.006 0.26

Appendicular lean mass (kg)prepost

14.3 ± 1.815.5 ± 2.2

15.7 ± 4.115.5 ± 4.0

0.002 0.33

Total body protein (kg)prepost

6.40 ± 2.028.20 ± 1.84

7.66 ± 3.567.25 ± 3.93

0.004 0.28

Total fat mass (kg)prepost

27.8 ± 12.025.5 ± 10.8

31.3 ± 8.729.9 ± 10.4

0.657

Trunk fat mass (kg)prepost

14.0 ± 6.511.5 ± 5.2

16.1 ± 5.714.8 ± 6.1

0.489

Effects of 24 wks high intensity PRT on body composition in RA patients

Variable PRT group(n=13)

ROM controls(n=15)

CachecticprePost

94

77

Obeseprepost

107

1212

Cachectic-obeseprepost

52

55

Lemmey et al., Arthritis & Rheum (2009) 61:1726-34

Effects of 24 wks high intensity PRT on physical function in RA patients

0

3

6

9

12

15

PRT Cont

50 f

t w

alk

(s)

0

3

6

9

12

15

PRT Cont

50 f

t w

alk

(s)

0

100

200

300

400

500

PRT Cont

Kn

ee

ext

enso

r st

ren

gth

(N

)

0

100

200

300

400

500

PRT Cont

Kn

ee

ext

enso

r st

ren

gth

(N

)

0

5

10

15

20

25

30

PRT Cont

Arm

Cu

rls

(re

ps

)

Pre

Post

0

3

6

9

12

15

18

21

PRT Cont

30s

sit

-to

-sta

nd

(re

ps)

A B

C D

****

*

**

0

5

10

15

20

25

30

PRT Cont

Arm

Cu

rls

(re

ps

)

Pre

Post

0

3

6

9

12

15

18

21

PRT Cont

30s

sit

-to

-sta

nd

(re

ps)

0

3

6

9

12

15

PRT Cont

50 f

t w

alk

(s)

0

100

200

300

400

500

PRT Cont

Kn

ee

ext

enso

r st

ren

gth

(N

)

A B

C D

****

*

**

0

5

10

15

20

25

30

PRT Cont

Arm

Cu

rls

(re

ps

)

Pre

Post

0

3

6

9

12

15

18

21

PRT Cont

30s

sit

-to

-sta

nd

(re

ps)

A B

C D

****

*

**

0

5

10

15

20

25

30

PRT Cont

Arm

Cu

rls

(re

ps

)

Pre

Post

0

3

6

9

12

15

18

21

PRT Cont

30s

sit

-to

-sta

nd

(re

ps)

0

3

6

9

12

15

PRT Cont

50 f

t w

alk

(s)

0

100

200

300

400

500

PRT Cont

Kn

ee

ext

enso

r st

ren

gth

(N

)

A B

C D

****

*

**

* p<0.05, ** p<0.01, *** p<0.001 (group x time interaction). Line represents “healthy control” values (gender and age weighted)

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

02468

10121416

IGF-І IGFBP-3

pg

/μg Controls

Patients

**

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

Oral mixture of amino acids:Arginine = 14 g/dayGlutamine = 14 g/dayβ-hydroxy-β-methylbutyrate(HMB) = 3 g/day

What is Juven?

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

0

100

200

300

400

500

600

Juven Placebo

gra

ms

Data presented as Mean ± SEM

(Main Factor Time P < 0.05)

Randomised Controlled Trial of Juven in RA Patients

7.0

7.5

8.0

8.5

9.0

9.5

10.0

10.5

11.0

Pretest Posttest

Tot

al b

ody

prot

ein,

kg

HMB/Arg/Glut Placebo

¶#

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

10

11

12

13

14

15

16

Pre Post

Sit-t

o-st

and

reps

in 3

0"

Juven

Placebo

Data presented as Mean ± SEM

(Main Factor Time P < 0.05)

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

Anabolic Steroids in RA: Women (Bird et al., 1987)

800850

900950

1000

105011001150

12001250

0 6 12 18 24

Month

TBN

(g)

Nandrolone

Control

*

Equivalent to 3 kg of FFM. Body mass did not change

* P < 0.01

Johansen et al., JAMA, 1999

-4

-3

-2

-1

0

1

2

3

4

5

Lean mass Fat mass

Ch

ang

e (k

g)

Placebo

NandroloneDecanoate

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 (Body-Image 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

-4

-2

0

2

4

6

8

10

12

0 50 100 200

Dose (mg/week)

AL

M c

ha

ng

e s

co

re (

%) * #

ALM, appendicular lean mass; *, p < 0.01 vs.. control; #, p < 0.01 vs.. low dose group.

Dose response of nandrolone on muscle mass

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)

Modified from 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