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Neural and Muscular Factors in Muscle Fatigue (Fatigability) of Older Adults: Role of Energetics

Neural and Muscular Factors in Muscle Fatigue (Fatigability) of Older Adults: Role of Energetics. Jane Kent-Braun, PhD Muscle Physiology Laboratory Department of Kinesiology University of Massachusetts, Amherst. Outline. Neuromuscular changes in old age

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Neural and Muscular Factors in Muscle Fatigue (Fatigability) of Older Adults: Role of Energetics

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  1. Neural and Muscular Factors in Muscle Fatigue (Fatigability) of Older Adults: Role of Energetics Jane Kent-Braun, PhD Muscle Physiology Laboratory Department of Kinesiology University of Massachusetts, Amherst

  2. Outline • Neuromuscular changes in old age • Measuring the mechanisms of human muscle fatigue in vivo • Basis of age-related differences in muscle fatigue • Integrating divergent results

  3. Skeletal Muscle Function • strength, power(sarcopenia) • activation; central, peripheral • contractile properties(fast, slow) • energetics(oxidative, glycolytic) • fatigue resistance (fall of max. force),endurance(time to task failure)

  4. Neuromuscular Changes in Old Age StructuralFunctional ↓ strength & power ↓ muscle size  voluntary activation ↑ intra-, extra-myocellular fat ↓max. discharge rates ↓motor unit number slowed contractile properties ↑ type I MHC content ↑ type I/type II fiber area peripheral activation  () oxidative capacity  capillarity ↑ oxidative energy utilization Fatigue Resistance? Note: all species decrease spontaneous physical activity in old age!

  5. Potential Sites of Fatigue in Vivo O2 delivery (blood flow) Central Activation rate coding recruitment modulation Peripheral Activation NMJ, membrane excitability conduction velocity muscle cell Contractile Function EC coupling Ca2+ kinetics cross-bridge function Metabolism energy supply inhibitory action Force or Power

  6. CNS NMJ stimulation Central & Peripheral Activation, Contractile Function Activation: process by which the signal to contract is transmitted from CNS to contractile apparatus

  7. Assessing the Sites Contractile Function Energetics Central Activation Peripheral Activation muscle cell Force

  8. Assessing the Sites EMG CAR Force 0 1000 2000 3000 4000 5000 Time (s) Contractile Function Energetics Peripheral Activation muscle cell Force

  9. Assessing the Sites EMG CAR Force m-wave 0 1000 2000 3000 4000 5000 Time (s) Contractile Function Energetics muscle cell Force

  10. Assessing the Sites EMG CAR Force m-wave 0 1000 2000 3000 4000 5000 Time (s) muscle cell Contractile Function 31P MRS Force ATP

  11. pH Intracellular Energy Metabolism Muscle Contraction:ATPADP+Pi+ energyCreatine kinase reaction:ADP+PCr+H+ ATP + Cr PCr Calculate: pH [ADP] [H2PO4-] [AMP] γ-ATP α-ATP Pi β-ATP

  12. In Vivo Muscle Energetics: 31P MRS • 4T whole-body system (Yale) • 2-12 s resolution • metabolites of fatigue • oxidative function • glycolytic flux recovery contraction rest

  13. Assessing the Sites in Vivo EMG CAR Force m-wave 0 1000 2000 3000 4000 5000 Time (s) 31P MRS Electrical stim. muscle cell ATP Force

  14. 4 Tesla MRS • In vivo and simultaneous • measures of: • activation • force, contractile • properties • energetics, acidosis • intracellular PO2 • perfusion

  15. Physical Activity Array Foulis, submitted Age-Based Differences in Muscle Fatigue Study groups: • young (21-40y), older (65-80y) • healthy (balanced by sex) • sedentary, activity-matched • older, physically-impaired Contraction protocols: • Maximal and submaximal contractions • Isometric and dynamic contractions • Effect of duty cycle (contraction/relaxation, 10 s) • Effect of blood flow • Effect of muscle group

  16. Study #1Fatigue During Incremental Contractions: Effect of Old Age? isometric, intermittent (40% duty cycle) 2 min stages for 16 min increments of 10% MVC from steady-state to fatigue activation, contractile function, energetics

  17. 20 Y, 21 O Target force Less fatigue in old than young Kent-Braun, 2002

  18. More intracellular acidosis in young 20 Y, 21 O pH Greater accumulation of Pi and H2PO4- in young

  19. OW OM YW YM Fatigue During Incremental Contractions Associated with [H2PO4-] Kent-Braun, 2002

  20. Time (min) H+ MRS: Greater Myoglobin Desaturation in Young Intracellular PO2 Y = 5.3 Torr O = 7.0 Torr (NS) n = 17 Y n = 18 O Wigmore, in prep

  21. Fatigue Resistance in Aging O2 delivery (blood flow) Central Activation Peripheral Activation muscle cell Contractile Function Energetics Force

  22. Study #2Pathways of ATP Production In Vivo:Effect of Old Age? isometric, maximal contraction for 60 s ATP production by: - oxidative phosphorylation (mitochondria) - glycolysis - creatine kinase reaction

  23. 40% Lower peak glycolytic rate in old during 60s MVC (p<0.001) Lanza et al, 2005 Energetic “Capacity” In Vivo Similar Vmax for oxidative phosphorylation in young and old (p = 0.67)

  24. Pathway UtilizationIn Vivo Young Greater reliance on oxidative metabolism in healthy old Older Lanza, 2005

  25. Study #3ATP Production in Young & Old:Oxidative “Preference” or Glycolytic Limitation? 6 isometric, maximal contractions intermittent (50% duty cycle; 12s/12s) +/- ischemia ATP flux by oxphos, glycolysis, CK

  26. intracellular pH Less Fatigue in Old During Maximal Contractions Free-flow force-time integral 40 Y, 38 O Ischemia 12s contract, 12s relax Lanza, 2007

  27. Free Flow young; r = 0.88  0.05 older; r = 0.82  0.07 Ischemia young; r = 0.90  0.05 older; r = 0.82  0.06 Fatigue During Maximal Contractions Associated with [H2PO4-] Lanza, 2007

  28. Higher Metabolic Economy in Older Adults During Maximal Isometric Contractions (free-flow)

  29. Study #4Is Oxygen Needed for Fatigue Resistance in the Elderly? 6 min intermittent, isometric MVCs free-flow, occlusion-reperfusion - central activation - peripheral activation - contractile properties

  30. Old FF Young FF Old IR Young IR Age-Related Difference in Muscle Fatigue More Apparent During Ischemia! O < Y (p=0.02) O < Y (p<0.01) O = Y (p=0.07) free-flow reperfusion ischemia Chung, 2007 more central & peripheral activation failure in young during ischemia

  31. Summary and Conclusions • Increased fatigue resistance in old age, during isometric contractions, has a metabolic basis (with secondary effects on central activation). • Energetic and fatigue differences in young and old are independent of blood flow. • Chronic neural (central) and contractile (peripheral) adaptations likely play a role in altered muscle energetics. • Lack of age-by-sex interactions suggests the neuromuscular systems of men and women age similarly.

  32. Muscular Component Neural Component Fiber type shift: relative ↑ type I fiber area ↓ Maximal motor unit discharge rates • - Slower force • relaxation • - Force fusion at • lower frequency Force produced with fewer motor unit discharges metabolic economy higher in type I fibers ↓ metabolic demand ↑ metabolic economy ↓ accumulation of inhibitory metabolites less fatigue Neural and Muscular Factors May Establish Metabolic Basis of Fatigue Resistance in Healthy Older Adults Kent-Braun, 2008

  33. Muscular Factors: ATP Cost of Twitch tibialis anterior, mean+SE Tevald, in progress

  34. Integrating Divergent Results?

  35. Poor Davies 1983 (e) Lennmarken 1985 Cupido 1992 (e) Petrella 2005 (d) Baudry 2006 (d) McNeil 2007 (d) Fatigue Resistance & Endurance: Older humans show… Same Klein 1988 (e) Cupido 1992 (e) Bemben 1996 Lindstrom 1997 (d) Stackhouse 2001 McNeil 2007 (d) Petrofsky 1975 Larsson 1978 Sperling 1980 Allman 2001 Yoon 2008 Better Narici 1991 (e) Bemben 1996 Ditor 2000 Chan 2000 Kent-Braun 2002 Lanza 2004 (d) Allman 2004 (e) Rubenstein 2005 Chung 2007 Lanza 2008 Bilodeau 2001 Hunter 2004, 2005 Mademli 2008 Yoon 2008 Fatigue Resistance Endurance (e) denotes stimulated contractions (d) denotes dynamic contractions

  36. Effect of Age on Fatigue Varies by Contraction Mode and Muscle Group Dorsiflexors Knee Extensors isometric dynamic Lanza et al, 2004 Callahan et al, ACSM 2008

  37. Mitochondrial Capacity Varies by Muscle kPCr (s-1) TA VL tibialis anterior vastus lateralis Older impaired group: SPPB ~10 Larsen, in preparation

  38. Difference in Mitochondrial Capacity by Muscle Related to Physical Activity Dose (and Health) Tibialis AnteriorVastus Lateralis r = 0.29 p = 0.07 r = 0.74 p < 0.001 Muscle Oxidative Capacity Daily Minutes of High-Intensity Activity n = 44 young and older adults Larsen et al, ACSM 2008

  39. Older Sedentary Older Impaired Physical Activity Arrays:Accelerometry Young Active Young Sedentary Zero Sedentary Light Moderate Vigorous Foulis, submitted

  40. Physical Activity (counts·day-1·1000-1) Daily Total Physical Activity Larsen, in preparation

  41. MVPA (min·day-1) Daily Minutes of Moderate-Vigorous Physical Activity Larsen, in preparation

  42. O = Y < OI Physically-Impaired Elders Lose Their Fatigue Resistance in the Knee Extensor Muscles Isometric Dynamic O < Y = OI Callahan, in progress

  43. healthy old impaired old Relative ability to resist fatigue in old age: Dependence on contraction velocity? 80% • intensity • duty cycle • muscle torque or power at fatigue (% baseline) young velocity very fast 0 Is greater fatigue resistance during isometric contractions in elderly eliminated or reversed during dynamic contractions?

  44. healthy old impaired old Absolute Amount of Fatigue: Implications for Physical Function? torque or power (Nm∙s-1) young functional deficit velocity Importance of baseline muscle strength! e.g., Lindstrom et al, 1997; Milner-Brown & Miller, 1989

  45.  physical activity  muscle mass  neural drive  muscle power  mitochondrial function loss of fatigue resistance  physical function  relative exertion, perceived fatigue Progression from Fatigue Resistance to Physical Impairment? injury/disease/event/age

  46. Collaborators University of Massachusetts, Amherst Ian Lanza, PhD David Russ, PT, PhD Danielle Wigmore, PhD Linda Chung, MS Damien Callahan, MS Stephen Foulis, MS Michael Tevald, PT, PhD Graham Caldwell, PhD Yale University Douglas Befroy, DPhil Douglas Rothman, PhD University of California, San Francisco Alexander Ng, PhD Julie Doyle, MS Support National Institute on Aging R01 AG21094, K02 AG023582 ACSM, AFAR, NASA, AHA, APTA

  47. Future Directions What do we need to know? 1. What is inevitable? - in healthy adults, with attention to activity level - range of ages (25-95 years) - biological aging; “what is the target?” 2. What is modifiable? - effects of impairment/disease, medications? - interactions between sarcopenia and fatigue? - multi-system studies (neural, contractile, energy…) - context of independent living

  48. Design Considerations A. Study populations health, activity, age, sex old, older, oldest? B. Protocols - capacity of the system (“biological aging”), or - typical conditions (“representative of population”)? - mode, intensity, frequency, duration, duty cycle - muscle(s) - definitions; endurance,  force/power,  velocity C. Mechanisms how to measure? molecular, single fiber, animal models?

  49. Similar Oxidative Potential in Young & Older Adults

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