1. Four Points: Fatigue 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 65%

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 2000;37:14-17. Cancer J 12:374-87, 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 2001;92:1699-1707.

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.

9. 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. Wessley and Powell, 1989 Scored 0, 1 or 2 by the patient so range is 0 to 26Scored 0, 1 or 2 by the patient so range is 0 to 16 for physical scale and 0 to 10 for mental scale

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 Perceived Effort Rating 0 10 Yoon,T etal. Muscle Nerve 37:457, 2008 Slope Young 0.6 + 0.2/min Slope Old 0.3 + 0.1/min p<0.05

13. 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

14. 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;

15. MVO 2max Post-Prandial and Other Thermogenesis Physical and Cognitive Activities (Walking, Talking, Watching, Thinking, etc.) Theoretical Minimum Energy Requirement For Homeostasis (Age, Sex, Body Composition and Physical Activity) Extra Energy for Unstable Homeostasis (Homeostatic Effort) An Extended Model of Energetic Frailty Fatigue 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 65%

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.

18. 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) Ventilation (L/min) Piepoli et al. Circulation 1996

19. ErgoReceptor May Be HyperActive in Heart Failure Piepoli et al. Circulation 1996

20. Ergoreceptors Mechano- Receptors Metabo- Receptors Group IV Afferents Unmyelinated VR1 receptors Capsacin augmented ? Blunted in CHF Group III Afferents Thinly Myelinated P2X receptors ATP augmented ? Augmented in CHF CNS? Substance P Tachykinin Williams CA, Brain Res 944:19 2002

21. Clark, A L Origin of symptoms in chronic heart failure Heart 2006;92:12–16. ErgoReceptor Stimulation May Produce Fatigue

22. 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

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 91:225, 2005

24. Training Desensitizes ErgoReceptors Piepoli et al. Circulation 1996

25. 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. MVO 2max Post-Prandial and Other Thermogenesis Physical and Cognitive Activities (Walking, Talking, Watching, Thinking, etc.) Theoretical Minimum Energy Requirement For Homeostasis (Age, Sex, Body Composition and Physical Activity) Extra Energy for Unstable Homeostasis (Homeostatic Effort) An Extended Model of Energetic Frailty Fatigue With thanks to Dr. Ferucci

27. MVO 2max Post-Prandial and Other Thermogenesis Physical and Cognitive Activities (Walking, Talking, Watching, Thinking, etc.) Theoretical Minimum Energy Requirement For Homeostasis (Age, Sex, Body Composition and Physical Activity) Extra Energy for Unstable Homeostasis (Homeostatic Effort) An Extended Model of Energetic Frailty Fatigue With thanks to Dr. Ferucci

28. AMP-Activated Protein Kinase: AMPK An Energy Charge Sensor

29. AMPKs 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 TZDs 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.

30. AMPK Regulates Energy State ATP -> ADP + Pi + work 2ADP -> ATP + AMP Jorgensen SB etal. J Physiol 2006 Glucose Uptake

31. 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?

32. 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

33. Mitochondrial Diseases

34. Johns, DR. NEJM 1995

35. Persons with Mitochondiral Mutations have Exercise Intolerance Jeppsen TD etal., J Neurol (2007) 254:29–37

36. 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: 2656–68.

38. 128+11 Control Values 25.2+2.2 67+2 1.05+.02 21.9+2.3 Lindholm H, etal. Clin Physiol Funct Imaging (2004) 24:109–115

39. 23-25 min 15 m/min 25 o incline 21-23 min 15 m/min 20 o incline 19-21 min 15 m/min 15 o incline 17-19 min 15 m/min 10 o incline 15-17 min 15 m/min 5 o incline 13-15 min 15 m/min 0 o incline 11-13 min 12 m/min 0 o incline 9-11 min 10 m/min 0 o incline 7-9 min 7 m/min 0 o incline 5-7 min 5 m/min 0 o incline 0-5 min Rest

40. 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: 2656–68.

42. L-Carnitine Reduces Physical Fatigue in Centenarians * L-Carnitine Reduces Mental Fatigue in Centenarians * Pre Post Carnitine Pre Post Placebo 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 <35 for males or <25 microM/L for females, or acyl/free carnitine ratio >0.4), Am J Clin Nutr 2007;86:1738–44.

43. 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

44. THE END