Download - Four Points: Fatigue George E. Taffet, M.D. Baylor College of Medicine The Methodist Hospital Houston, Texas

Four Points:Fatigue

George E. Taffet, M.D.Baylor College of Medicine

The Methodist HospitalHouston, Texas

Outline

• “Definition of Fatigue” Issues

• Ergoreceptors

• AMPK

• Mitochondrial diseases

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

Fatigue is Very Common in Older Persons with CHF

Fatigue Correlated with Perceived High Symptom Burden

Barnes S, etal. J Pain Symptom Manage 2006

65%

What Might Fatigue Be?

• Tiredness at rest

• Easy fatiguabilty with exertion

• Inability to maintain same level of performance with continued exertion

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 2000;37:14-17.

Cancer J 12:374-87, 2006

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 2001;92:1699-1707.

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.

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.

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.

Holding a 20% contraction becomes Harder with time

Perceived Effort Rating

0

10

Yoon,T etal. Muscle Nerve 37:457, 2008

Slope Young 0.6 + 0.2/minSlope Old 0.3 + 0.1/minp<0.05

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: 191–197

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: 287–332, 2008;

MVO2maxPost-Prandial andOther Thermogenesis

Physical and CognitiveActivities(Walking, Talking,Watching, Thinking, etc.)

Theoretical MinimumEnergy Requirement For Homeostasis(Age, Sex, BodyComposition and Physical Activity)

Extra Energy forUnstable Homeostasis(Homeostatic Effort)

An Extended Model of Energetic Frailty

Fatigue

With thanks to Dr. Ferucci

Fatigue is Very Common in Older Persons with CHF

Fatigue Correlated with Perceived High Symptom Burden

Barnes S, etal. J Pain Symptom Manage 2006

65%

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.”

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).

There is a Receptor that Assesses Work/Fatigue (ErgoReceptor)

Ven

tilat

ion

(L/m

in)

Piepoli et al. Circulation 1996

ErgoReceptor May Be HyperActive in Heart Failure


Ergoreceptors

Mechano-Receptors

Metabo-Receptors

Group IV AfferentsUnmyelinatedVR1 receptorsCapsacin augmented? Blunted in CHF

Group III AfferentsThinly MyelinatedP2X receptorsATP augmented? Augmented in CHF

CNS?

Substance PTachykinin

Williams CA, Brain Res 944:192002

Clark, A L Origin of symptoms in chronic heart failureHeart 2006;92:12–16.

ErgoReceptor Stimulation May Produce Fatigue

What Triggers the ErgoReceptor Hyperresponsiveness?

• Inactivity

• Activation of Renin/Angiotensin

• Activation of Sympathetic Nervous System

• Inadequate Nutrient Blood Flow

• Cytokines: TNF-α, IL-6, etc..

• Myocardial Infarction

• Other potential mechanisms

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 91:225, 2005

Training Desensitizes ErgoReceptors


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?

MVO2maxPost-Prandial andOther Thermogenesis

Physical and CognitiveActivities(Walking, Talking,Watching, Thinking, etc.)

Theoretical MinimumEnergy Requirement For Homeostasis(Age, Sex, BodyComposition and Physical Activity)

Extra Energy forUnstable Homeostasis(Homeostatic Effort)

An Extended Model of Energetic Frailty

Fatigue

With thanks to Dr. Ferucci

AMP-Activated Protein Kinase:AMPK

An Energy Charge Sensor

AMPK’s are • Heterotrimeric complex of a catalytic, α-subunit (α1 or α2),

a β-(scaffold) subunit (β 1, β 2, β 3) and a “regulatory” γ-subunit (γ 1, γ 2 or γ 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 TZD’s and regulated by TGF- β-activated kinase-1 (TAK1)

Rutter, G.A., Leclerc, I., The AMP-regulated kinase family…. Mol. Cell. Endocrinol. (2008)Hardie, DG. AMP-Activated Protein Kinase…Med. Sci. Sports Exerc.,36: 28–34, 2004.

AMPK Regulates Energy StateATP -> ADP + Pi + work2ADP -> ATP + AMP

Jorgensen SB etal. J Physiol 2006Glucose Uptake

AMPK

• Data obtained in the α1- or α2-AMPK knockout models, in which ex vivo contraction-stimulated glucose uptake and force production is normal.

• α2-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?

AICAR in the Mouse • 5-amino-4-imidazolecarboxamide riboside

(AICAR) is an adenosine analogue that can activate AMPK

• if both α1- and α2-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: 405–415, 2008

Mitochondrial Diseases

Johns, DR. NEJM 1995

Persons with Mitochondiral Mutations have Exercise Intolerance

Jeppsen TD etal., J Neurol (2007) 254:29–37

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.

DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348: 2656–68.

128+11Control Values25.2+2.2

67+2

1.05+.02

21.9+2.3

Lindholm H, etal. Clin Physiol Funct Imaging (2004) 24:109–115

• 23-25 min 15 m/min 25o incline• 21-23 min 15 m/min 20o incline• 19-21 min 15 m/min 15o incline • 17-19 min 15 m/min 10o incline • 15-17 min 15 m/min 5o incline • 13-15 min 15 m/min 0o incline • 11-13 min 12 m/min 0o incline • 9-11 min 10 m/min 0o incline • 7-9 min 7 m/min 0o incline • 5-7 min 5 m/min 0o incline • 0-5 min Rest

DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348: 2656–68.

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10121416

1 2

L-Carnitine Reduces PhysicalFatigue in Centenarians

*

0

2

4

6

8

10

1 2

L-Carnitine Reduces MentalFatigue in Centenarians

*

Pre PostCarnitine

Pre PostPlacebo

66 Centenarians (32 active, 34 placebo)given 2 g L-Carnitine daily for 6 mos.Mean age 101 for both groupsReduced fatigueAlso Reduced Fatigue Serverity ScoreIncreased 6 min walk(from Department of Senescence, Urological, and

Neurological Sciences, University of Catania, Catania, Italy). 3 Positive Open Label studies forCancer Related Fatigue1 Positive Open Label in 80 year olds4 weeks of 2 g BIDCarnitine deficiency (free carnitine <35for males or <25 microM/L for females, or acyl/free carnitine ratio >0.4),

Am J Clin Nutr 2007;86:1738–44.

Wessley and Powell, 1989

Scored 0, 1 or 2 by the patient so range is 0 to 16 for physical scale and 0 to 10 for mental scale

•THE END

Download - Four Points: Fatigue George E. Taffet, M.D. Baylor College of Medicine The Methodist Hospital Houston, Texas

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