Four Points: Fatigue

1
Four PointsFatigue

• George E. Taffet, M.D.
• Baylor College of Medicine
• The Methodist Hospital
• Houston, Texas

2
Outline

• Definition of Fatigue Issues
• Ergoreceptors
• AMPK
• Mitochondrial diseases

3
Fatigue?

• A broad array of clinical conditions is
  associated with extreme levels of fatigue.
• chronic renal failure
• congestive heart failure
• cancer
• musculoskeletal diseases
• chronic fatigue syndrome
• chronic obstructive pulmonary disease
• HIV/AIDs

4
Fatigue is Very Common in Older Persons with CHF
Fatigue Correlated with Perceived High Symptom
Burden
Barnes S, etal. J Pain Symptom Manage 2006
5
What Might Fatigue Be?

• Tiredness at rest
• Easy fatiguabilty with exertion
• Inability to maintain same level of performance
  with continued exertion

6
Mitchell and Berger Definition

• fatigue is a multifaceted condition
  characterized by diminished energy and an
  increased need to rest, disproportionate to any
  recent change in activity level, and accompanied
  by a range of other characteristics, including
  generalized weakness, diminished mental
  concentration, insomnia or hypersomnia, and
  emotional reactivity.
• Curt GA. Impact of fatigue on quality of life in
  oncology patients.
• Semin Hematol 20003714-17.

Cancer J 12374-87, 2006
7
Mock Definition

• persistent and subjective sense of tiredness
  that interferes with usual functioning.
• Fatigue may represent a final common pathway to
  which many predisposing or etiologic factors
  contribute.
• Mock V. Fatigue management evidence and
  guidelines for practice. Cancer 2001921699-1707.

8
Bill Evans Operational Definition

• Fatigue is physical and/or mental weariness
  resulting from exertion, that is, an inability to
  continue exercise at the same intensity with a
  resultant deterioration in performance.

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ICD-10 Criteria for (Cancer-Related) Fatigue

• The following symptoms have been present every
  day or nearly every day during the same 2-week
  period in the past month
• Significant fatigue, diminished energy, or
  increased need to rest, disproportionate to any
  recent change in activity level, plus five or
  more of the following
• Complaints of generalized weakness, limb
  heaviness.
• Diminished concentration or attention.
• Decreased motivation or interest to engage in
  usual activities.
• Insomnia or hypersomnia.
• Experience of sleep as unrefreshing or
  nonrestorative.
• Perceived need to struggle to overcome
  inactivity.
• Marked emotional reactivity (e.g., sadness,
  frustration, or irritability) to feeling
  fatigued.
• Difficulty completing daily tasks attributed to
  feeling fatigued.
• Perceived problems with short-term memory.
• Postexertional fatigue lasting several hours.
• The symptoms cause distress or impair social,
  occupational, or other function.
• There is evidence from the history, physical
  examination, or laboratory findings that the
  symptoms are a consequence of cancer or cancer
  therapy.
• The symptoms are not primarily a consequence of
  comorbid psychiatric disorders such as major
  depression, somatization disorder, somatoform
  disorder, or delirium.

10
Scored 0, 1 or 2 by the patient so range is 0 to
26
Scored 0, 1 or 2 by the patient so range is 0 to
16 for physical scale and 0 to 10 for mental
scale
Wessley and Powell, 1989
11
What Might Fatigue Be?

• Tiredness at rest
• Easy fatiguabilty with exertion
• Inability to maintain same level of performance
  with continued exertion
• or my definition
• Inability to maintain level of performance with
  the same perceived level of exertion.

12
Holding a 20 contraction becomes Harder with time
10
Slope Young 0.6 0.2/min Slope Old 0.3
0.1/min plt0.05
0
Yoon,T etal. Muscle Nerve 37457, 2008
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Older Men May Perceive Greater Effort above 50
MVC
Allman, BL and Rice CL Perceived exertion is
elevated in old age during an isometric fatigue
task. Eur J Appl Physiol (2003) 89 191197
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Sensing Fatigue?

• Presumably to achieve the necessary force for a
  particular activity, the brain must increase the
  firing rate or activate more motor units for a
  particular muscle and interprets this information
  as weakness (or fatigue), even though the muscle
  may show no decrement in force
• Implicit in this conceptualization is that you
  cannot be fatigued at rest.

Allen, DG. etal. Physiol Rev 88 287332, 2008
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An Extended Model of Energetic Frailty
MVO2max
Post-Prandial and Other Thermogenesis
Physical and Cognitive Activities (Walking,
Talking, Watching, Thinking, etc.)
Fatigue
Extra Energy for Unstable Homeostasis (Homeostatic
Effort)
Theoretical Minimum Energy Requirement For
Homeostasis (Age, Sex, Body Composition and
Physical Activity)
With thanks to Dr. Ferucci
16
Fatigue is Very Common in Older Persons with CHF
Fatigue Correlated with Perceived High Symptom
Burden
Barnes S, etal. J Pain Symptom Manage 2006
17
Clark BMJ

• A unifying hypothesis, then, is that skeletal
  muscle becomes abnormal in chronic heart
  failure..In turn, this leads to abnormal muscle
  performance during exercise, objectively seen as
  reduced strength and endurance and subjectively
  felt as the sensation of fatigue.

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There is a Receptor that Assesses Work/Fatigue
(ErgoReceptor)
Handgrip dynamometer exercise to exhaustion
finishes at the beginning of the shaded panel. A
cuff is either inflated around the exercising arm
at peak exercise (filled symbols) or not (open
symbols). The cuff is deflated after three
minutes (end of shaded panel).
Ventilation (L/min)
Piepoli et al. Circulation 1996
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ErgoReceptor May Be HyperActive in Heart Failure
Piepoli et al. Circulation 1996
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Ergoreceptors
CNS? Substance P Tachykinin
Williams CA, Brain Res 94419 2002
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ErgoReceptor Stimulation May Produce Fatigue
Clark, A L Origin of symptoms in chronic heart
failure Heart 2006921216.
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What Triggers the ErgoReceptor Hyperresponsiveness
?

• Inactivity
• Activation of Renin/Angiotensin
• Activation of Sympathetic Nervous System
• Inadequate Nutrient Blood Flow
• Cytokines TNF-a, IL-6, etc..
• Myocardial Infarction
• Other potential mechanisms

23
Fatigue Breathlessness??

• Cycle based exercise led to patients and controls
  stopping exercise more frequently because of
  fatigue rather than breathlessness (15 v 7 for
  cycle and 10 v 12 for treadmill, p , 0.05).
• Does weight-bearing during treadmill exercise
  causes greater ergoreflex activation or the
  amount of muscle being used?

Witte KKA etal. Heart 91225, 2005
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Training Desensitizes ErgoReceptors
Piepoli et al. Circulation 1996
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Summary

• Ergoreceptors sense work performed by muscle
• Ergoreceptors are hyper-responsive in CHF leading
  to augmented responses to very modest efforts
  including exaggerated perception of effort
• Ergoreceptor normalization via training or drugs
  may be a beneficial approach to improving quality
  of life including fatigue in people with heart
  failure
• Are ergoreceptors potential targets to ameliorate
  fatigue?

26
An Extended Model of Energetic Frailty
MVO2max
Post-Prandial and Other Thermogenesis
Physical and Cognitive Activities (Walking,
Talking, Watching, Thinking, etc.)
Fatigue
Extra Energy for Unstable Homeostasis (Homeostatic
Effort)
Theoretical Minimum Energy Requirement For
Homeostasis (Age, Sex, Body Composition and
Physical Activity)
With thanks to Dr. Ferucci
27
An Extended Model of Energetic Frailty
MVO2max
Post-Prandial and Other Thermogenesis
Physical and Cognitive Activities (Walking,
Talking, Watching, Thinking, etc.)
Fatigue
Extra Energy for Unstable Homeostasis (Homeostatic
Effort)
Theoretical Minimum Energy Requirement For
Homeostasis (Age, Sex, Body Composition and
Physical Activity)
With thanks to Dr. Ferucci
28
AMP-Activated Protein KinaseAMPKAn Energy
Charge Sensor
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AMPKs are

• Heterotrimeric complex of a catalytic, a-subunit
  (a1 or a2), a ß-(scaffold) subunit (ß 1, ß 2, ß
  3) and a regulatory ?-subunit (? 1, ? 2 or ?
  3).
• AMPK may control whole body metabolic homeostasis
• fuel gauge or cellular energy sensor
• Key glucose and fatty acid metabolic role
• AMPK implicated in control
• fatty acid release from adipocytes
• pancreatic-cell function
• hypothalamic satiety centers involved in the
  control of feeding
• concurrently decreasing cellular energy-consuming
  anabolic processes
• Also activated by metformin and TZDs and
  regulated by TGF- ß-activated kinase-1 (TAK1)

Rutter, G.A., Leclerc, I., The AMP-regulated
kinase family. Mol. Cell. Endocrinol.
(2008) Hardie, DG. AMP-Activated Protein
KinaseMed. Sci. Sports Exerc.,36 2834, 2004.
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AMPK Regulates Energy State
Jorgensen SB etal. J Physiol 2006
Glucose Uptake
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AMPK

• Data obtained in the a1- or a2-AMPK knockout
  models, in which ex vivo contraction-stimulated
  glucose uptake and force production is normal.
• a2-KO mouse has a disturbed muscle energy balance
  during more prolonged exercise with reduced ATP
  content and a comparable increase in IMP.
• Activation of AMPK decreases protein synthesis
• Especially myofibrillar protein
• Good short term adaptation, bad long term?

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AICAR in the Mouse

• 5-amino-4-imidazolecarboxamide riboside (AICAR)
  is an adenosine analogue that can activate AMPK
• if both a1- and a2-AMPK activity are markedly
  decreased then contraction-(or AICAR) induced
  glucose uptake is diminished
• Activation of AMPK by AICAR increases plasma
  membrane content of GLUT4
• Activation of AMPK increased endurance (AICAR
  (500 mg/kg/day, 4 weeks), but inhibits mTOR
  pathway of protein synthesis
• No way to assess fatigue in these mice

Narkar, VA etal., AMPK and PPARd Agonists Are
Exercise Mimetics Cell 134 405415, 2008
33
Mitochondrial Diseases
34
Johns, DR. NEJM 1995
35
Persons with Mitochondiral Mutations have
Exercise Intolerance
Jeppsen TD etal., J Neurol (2007) 2542937
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Mito Diseases

• Mitochondrial disease may present with any
  symptom in any organ at any age
• Primary mitochondrial disease caused by
  mutations in nDNA or mtDNA directly impacts the
  composition and function of the electron
  transport chain and impairs mitochondrial
  oxidative phosphorylation and production of ATP.
• Isolated myopathic or cardiomyopathy
  presentations, frequently with exercise
  intolerance, are common in teenagers and young
  adults. (the more severe the metabolic disorder,
  the earlier it presents in life)
• Australian group combined adult prevalence
  figures with childhood figures to estimate a
  birth prevalence of 1 in 7634 live births or a
  lifetime risk of developing mitochondrial disease
  of 1 in 5000 live births.

37
DiMauro S, Schon EA. Mitochondrial
respiratory-chain diseases. N Engl J Med 2003
348 265668.
38
Lindholm H, etal. Clin Physiol Funct Imaging
(2004) 24109115
39
(No Transcript)
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Treatment for mitochondrial disorders

• P L A I N L A N G U A G E S U M M A R Y
• No clear evidence from randomised trials for the
  use of any intervention in mitochondrial
  disorders

Chinnery P, Majamaa K, Turnbull D, Thorburn
D Cochrane Systematic Reviews
41
DiMauro S, Schon EA. Mitochondrial
respiratory-chain diseases. N Engl J Med 2003
348 265668.
42
66 Centenarians (32 active, 34 placebo) given 2 g
L-Carnitine daily for 6 mos. Mean age 101 for
both groups Reduced fatigue Also Reduced Fatigue
Serverity Score Increased 6 min walk (from
Department of Senescence, Urological, and
Neurological Sciences, University of Catania,
Catania, Italy). 3 Positive Open Label studies
for Cancer Related Fatigue 1 Positive Open Label
in 80 year olds 4 weeks of 2 g BID Carnitine
deficiency (free carnitine lt35 for males or lt25
microM/L for females, or acyl/free carnitine
ratio gt0.4),
Am J Clin Nutr 200786173844.
43
Scored 0, 1 or 2 by the patient so range is 0 to
16 for physical scale and 0 to 10 for mental
scale
Wessley and Powell, 1989
44

• THE END