Neural and Muscular Factors in Muscle Fatigue Fatigability

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

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

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)

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

Potential Sites of Fatigue in Vivo Central Activation rate coding recruitment modulation Peripheral Activation NMJ, membrane excitability conduction velocity muscle cell Metabolism energy supply inhibitory action O 2 delivery (blood flow) Contractile Function EC coupling Ca 2+ kinetics cross-bridge function Force or Power

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

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

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

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

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

Intracellular Energy Metabolism Muscle Contraction: ATP ADP + Pi + energy PCr Creatine kinase reaction: ADP + PCr + H+ ATP + Cr p. H γ-ATP Pi α-ATP β-ATP Calculate: p. H [ADP] [H 2 PO 4 -] [AMP]

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

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

4 Tesla MRS In vivo and simultaneous measures of: • activation • force, contractile properties • energetics, acidosis • intracellular PO 2 • perfusion

Age-Based Differences in Muscle Fatigue Study groups: • • Physical Activity Array young (21 -40 y), older (65 -80 y) 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 Foulis, submitted

Study #1 Fatigue 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

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

More intracellular acidosis in young 20 Y, 21 O p. H Greater accumulation of Pi and H 2 PO 4 - in young

Fatigue During Incremental Contractions Associated with [H 2 PO 4 -] OM OW YM YW Kent-Braun, 2002

H+ MRS: Greater Myoglobin Desaturation in Young Intracellular PO 2 Y = 5. 3 Torr O = 7. 0 Torr (NS) n = 17 Y n = 18 O Time (min) Wigmore, in prep

Fatigue Resistance in Aging Central Activation Peripheral Activation muscle cell Energetics Contractile Function O 2 delivery (blood flow) Force

Study #2 Pathways 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

Energetic “Capacity” In Vivo Similar Vmax for oxidative phosphorylation in young and old (p = 0. 67) 40% Lower peak glycolytic rate in old during 60 s MVC (p<0. 001) Lanza et al, 2005

Pathway Utilization In Vivo Young Greater reliance on oxidative metabolism in healthy old Older Lanza, 2005

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

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

Fatigue During Maximal Contractions Associated with [H 2 PO 4 -] 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 Lanza, 2007

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

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

Age-Related Difference in Muscle Fatigue More Apparent During Ischemia! free-flow O < Y (p=0. 02) O < Y (p<0. 01) O = Y (p=0. 07) Old FF Young FF Old IR Young IR ischemia reperfusion Chung, 2007 more central & peripheral activation failure in young during ischemia

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.

Neural and Muscular Factors May Establish Metabolic Basis of Fatigue Resistance in Healthy Older Adults 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 Kent-Braun, 2008 ↓ accumulation of inhibitory metabolites less fatigue

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

Integrating Divergent Results?

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

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

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

Difference in Mitochondrial Capacity by Muscle Related to Physical Activity Dose (and Health) Tibialis Anterior Muscle Oxidative Capacity r = 0. 29 p = 0. 07 Vastus Lateralis r = 0. 74 p < 0. 001 Daily Minutes of High-Intensity Activity n = 44 young and older adults Larsen et al, ACSM 2008

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

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

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

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

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

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

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

Collaborators University of Massachusetts, Amherst Ian Lanza, Ph. D David Russ, PT, Ph. D Danielle Wigmore, Ph. D Linda Chung, MS Damien Callahan, MS Stephen Foulis, MS Michael Tevald, PT, Ph. D Graham Caldwell, Ph. D Yale University Douglas Befroy, DPhil Douglas Rothman, Ph. D University of California, San Francisco Alexander Ng, Ph. D Julie Doyle, MS Support National Institute on Aging R 01 AG 21094, K 02 AG 023582 ACSM, AFAR, NASA, AHA, APTA

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

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?

Similar Oxidative Potential in Young & Older Adults

Effect of Contraction Velocity: Mechanisms? • Central? • ability to rapidly modulate MU behavior? • slowing of voluntary contraction/relaxation speeds? • coordination of agonists & antagonists? • Peripheral? • slowed contractile properties at baseline • no effect of age on degree of (additional) slowing during fatigue