Muscle wasting associated with chronic disease and ageing

1
Muscle wasting associated with chronic disease
and ageing

• Dr. Andrew Lemmey
• School of Sport, Health and Exercise Sciences
  (SSHES)
• Bangor University

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Cachexia / sarcopenia is associated with poor
outcome
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HD patients Body composition functional
capacity rs
Data are Pearsons r correlation coefficients.
, p lt 0.001.
Macdonald et al., J Renal Nutr 200414248-52
4
Functional capacity in haemodialysis patients
, p lt 0.05 from healthy controls
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Consequences of Sarcopenia Disability(Baumgartne
r, 2000)
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Consequences of Sarcopenia Mortality(Kotler et
al., 1989)
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Muscle Loss Secondary to Systemic Disease
Marcora et al., J. Rheumatol 2005321031-9
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(No Transcript)
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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 gt3k

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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

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Standard medical treatment does not completely
prevent muscle loss e.g. rheumatoid cachexia
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Anabolic Therapies

• PresentExercise training esp. progressive
  resistance training (PRT)Dietary
  supplementsAnabolic hormones
• FutureVarious combinations of the
  aboveAnti-myostatin therapyGene therapy

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Progressive Resistance Training
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Intense Progressive Resistance Training
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Can 24 wks progressive resistance training
reverse cachexia in rheumatoid arthritis
patients? A RCT
Lemmey et al., Arthritis Rheum In press
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Exercise Dose
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Very Intense!!!
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Effects of 24 wks high intensity PRT on body
composition in RA patients
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Effects of 24 wks high intensity PRT on body
composition in RA patients
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Effects of 24 wks high intensity PRT on physical
function in RA patients
plt0.05, plt0.01, plt0.001 (group x time
interaction). Line represents healthy control
values (gender and age weighted)
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Summary and Conclusions

• Muscle loss is an important consequence of
  chronic disease and ageing, and needs to be
  monitored (i.e. body composition assessment
  bioelectrical impedance offers a clinically
  appropriate method)
• Standard drug therapy, including anti-TNF
  therapy, neither completely prevents muscle
  wasting, nor restores muscle mass
• Thus, anabolic therapy in patients with cachexia
  is required e.g. high intensity exercise training
• The appropriate anabolic therapy may be
  conditional on the patients condition

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• The identification of effective means of treating
  sarcopenia/cachexia (muscle wasting) is very
  important since increasing muscle mass in
  individuals with severe muscle loss secondary to
  disease /or advanced ageing has the potential to
  decrease disability and morbidity, increase life
  expectancy, and improve quality of life in these
  patients

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Muscle Atrophy at Admission and Length of Stay in
Hospital
High FFMI
Normal FFMI
Low FFMI
Pichard et al. (2004)
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Muscle Loss Secondary to Drug Therapy(Androgen
Deprivation Therapy in Prostate Cancer Patients)
Smith et al. (2001)
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Objective Functional Capacity Tests
Rickli Jones, Senior Fitness Test Manual, Human
Kinetics (2001)
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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)
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Muscle Protein Metabolism inHealth and Disease
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Skeletal muscle IGF-? and IGFBP-3 levels
(normalized for total protein content) for 5
healthy controls and 7 HD patients. Values are
mean SD. , p lt 0.001 from healthy controls
(Macdonald et al., J Renal Nutr (2004).
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Anabolic Hormones
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• 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, anthropometry), BMD
  at neck of femur, lumbar spine (L2-L4)
• Physical function (30 sec SST, arm curl, 8 up
  go, 6 min walk)

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Anti-TNF Therapy in RA
Immunex Corporation andWyeth-Ayerst
PharmaceuticalsWashington, USA
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Role of Anti-TNF Therapy with Etanercept in
Preventing Muscle Wasting in RA Patients

• Single-blind, randomised, parallel, controlled
  trial
• 24 patients (mean age 52 13) with early (lt 6
  months) and active RA randomly assigned to
• A) 25 mg of etanercept sc twice a week (9 F, 3 M)
• B) 10 to 20 mg methotrexate once a week (9 F, 3
  M)
• Duration 24 weeks
• Body composition by DXA and BIS
• Objective (hand grip strength and functional
  tests) and subjective (HAQ) functional capacity
• Disease activity
• Growth factors

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Effect on Appendicular Lean Mass
Group x time interaction, P 0.16 Main
effect for time, P 0.26
Marcora et al., Am J Clin Nutr 2006841463-72
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?
Sarcopenia
?
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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)
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Comparison between etanercept and methotrexate in
preventing muscle loss in early rheumatoid
arthritis G Mittal1, K Chester2, A Lemmey2, P
Maddison1, S Marcora2 Department of Rheumatology,
Ysbyty Gwynedd1, and School of Sport, Health and
Exercise Science, University of Wales, Bangor2
Background Significant muscle loss is common in
rheumatoid arthritis (RA), occurs early and
progresses despite antirheumatic drug therapy. It
results from an imbalance between catabolic and
anabolic processes in which pro-inflammatory
cytokines play an important role. It makes a
major contribution to poor outcome and disability
Results change in disease activity and function
at 24 weeks Significant main effects
for time were observed for DAS (plt0.001), HAQ
(plt0.001), functional capacity (Chair test,
plt0.001) and SF36-phys (p0.001). No significant
difference was seen between the two treatment
groups Results mean change in muscle mass
(ASMM) at 24weeks A mixed model
ANOVA (group x time) revealed no significant
difference for ASMM between the ETN and MTX
groups over 24 weeks (p0.11)

• Results change in body composition in patients
  in positive energy balance at
• 24 weeks
• A sub analysis was performed on 12 patients who
  gained weight over 24 weeks
• In patients on ETN, 44 of body mass gained was
  fat free mass (FFM) compared with 14 in patients
  on MTX (p0.04)

Aim of study To compare the effect of etanercept
(ETN), a specific anti-TNF-a agent, with
methotrexate (MTX) in preventing muscle loss over
24 weeks in patients with RA.
Methods 24 recent onset RA patients randomised to
24 wks treatment with ETN 25mg twice a week or
MTX, rapidly escalated to an effective, tolerated
dose (19 3mg/week). Body composition, including
appendicular skeletal muscle mass (ASMM), was
estimated by whole body DEXA (Hologic QDR 1500)

1Baumgartner et al. Am J Epidemiol 1998
147755 DAS disease activity score HAQ health
assessment questionnaire SF36-phys physical
component summary scale of SF36
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Randomised Controlled Trial of Juven in RA
Patients
What is Juven?

• Oral mixture of amino acidsArginine 14
  g/dayGlutamine 14 g/dayß-hydroxy-ß-methylbutyr
  ate(HMB) 3 g/day

Marcora et al., Clinical Nutrition (2005)
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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

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Changes in Appendicular Muscle Mass
(Main Factor Time P lt 0.05)
Data presented as Mean SEM
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Randomised Controlled Trial of Juven in RA
Patients
Non significant group x time interaction P
0.74, ?2 0.00 Significant main effect for
time P 0.02, ?2 0.16
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Changes in Lower Body Function
(Main Factor Time P lt 0.05)
Data presented as Mean SEM
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Disease-Disability Pathways in RA
Escalante and del Rincon (2002)
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Escalante and del Rincon (1999)
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Rheumatoid Cachexia-Disability Pathway
Ageing
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Proportion of variance in physical disability in
RA explained by each variable measured, when
entered in the order of the RA disablement
pathway (hierarchical regression)
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Can progressive resistance training reverse
rheumatoid cachexia? A Phase II Trial
Marcora et al., J. Rheumatol (2005)
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Results Body Composition
FM Fat Mass LM Lean Mass. Significance was
tested by ANCOVA on follow-up scores using
baseline scores as covariate.
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Results Muscle Strength
Significance was tested by ANCOVA on follow-up
scores using baseline scores as covariate.
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Significant decrease (-0.25 HAQ score) in
disability (P 0.01) by ANCOVA
r -0.50, P 0.03
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• Drs. Andrew Lemmey, Sam Marcora, Jeanette Thom,
  SSHES
• Prof. Peter Maddison, Dr. Jerry Jones, Dr.
  Yasmeen Ahmed Rheumatology Dept., Ysbyty Gwynedd
  SSHES
• Dr. Gayatri Mittal, Ross Clinical Research
  Fellow, Dr. Rao Elamamchi, Dr. Verena Matschke
  Rheumatology Dept., Ysbyty Gwynedd
• Dr. Mardi Jibani, Renal Unit, Ysbyty Gwynedd Dr.
  Mick Kumwenda, Renal Unit, Ysbyty Glan Clywd
• Kathryn Chester, Francesco Casanova, research
  assistants. Ruth Glover, renal research nurse.
• PhD students Kath Chester, Jamie Macdonald,
  Francesco Casanova, Dr. Verena Matschke plus MSc
  and intercollated degree students (i.e. medical
  students)
• Prof. Nick Stuart, Oncology, Ysbyty Gwynedd
• Dr. Tony Wilton, Endocrinology, Ysbyty Gwynedd
• Prof. Jeff Holly, Division of Surgery, University
  of Bristol
• Prof. Claire Stewart, Dept. of Exercise and Sport
  Science, MMU