Skeletal Muscle Function Changes with Aging and Exercise: From the Myosin Molecule to the Whole Muscle

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1 University of Massachusetts Medical School UMass Center for Clinical and Translational Science Research Retreat 2016 UMass Center for Clinical and Translational Science Research Retreat May 20th, 11:15 AM Skeletal Muscle Function Changes with Aging and Exercise: From the Myosin Molecule to the Whole Muscle Mark S. Miller University of Massachusetts Amherst Follow this and additional works at: Part of the Cellular and Molecular Physiology Commons, and the Kinesiology Commons This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License. Miller, Mark S., "Skeletal Muscle Function Changes with Aging and Exercise: From the Myosin Molecule to the Whole Muscle" (2016). UMass Center for Clinical and Translational Science Research Retreat This material is brought to you by escholarship@umms. It has been accepted for inclusion in UMass Center for Clinical and Translational Science Research Retreat by an authorized administrator of escholarship@umms. For more information, please contact Lisa.Palmer@umassmed.edu.

2 Skeletal Muscle Function Changes with Aging and Exercise: From the Myosin Molecule to the Whole Muscle M.S. Miller Kinesiology, University of Massachusetts, Amherst, MA

3 Disclosure I have no actual or potential conflict of interest in relation to this presentation.

4 Areas of expertise Molecular level Myofibrillar level Muscle Function Single fiber level Single fiber level Whole muscle level Muscle Structure Whole muscle level Whole body level

5 Previous studies Aging Heart Failure Cancer Knee Osteoarthritis (disuse model) Heart Failure + Resistance training Knee Osteoarthritis + Resistance training (Submitted)

6 Why study myosin-actin interactions in aging skeletal muscle? Whole skeletal muscle power output decreases with age, which leads to functional limitations and disability Understanding mechanisms behind muscle power loss will aid in developing pharmacological and/or exercise countermeasures Power = Force Velocity Young Older Whole muscle size: Aging Loss of muscle quantity (muscle atrophy) Single fiber performance: Force Velocity Loss of muscle quality Are myosin-actin interactions affected by age? If so, can these altered myosin-actin interactions explain reductions in whole muscle power output?

7 Molecular level Age-related changes in muscle function Single fiber level Whole muscle level Whole body level Physical activity Functional performance (peak O 2 consumption)

8 Myosin-actin interactions or cross-bridge kinetics Myosin on Myosin detachment time (t off ) Myosin attachment time (t on ) Myosin off F XB Force Time Vale and Milligan (2000) Science

9 Myosin-actin cross-bridge kinetics Myosin on Myosin detachment time (t off ) Myosin attachment time (t on ) F XB Myosin off Force Time Force: 2 myosin heads Myosin head number (N) Time

10 Myosin-actin cross-bridge kinetics Myosin detachment time (t off ) Myosin attachment time (t on ) Myosin on F XB Myosin off t Isometric force (F Iso ): on F Iso = N F t XB on + t off Velocity 1 t on Force (F Iso ): F XB = 2 F XB Velocity: 1.0 ML/s Myosin head number (N) Time MHC I MHC IIA MHC IIX Shortening Velocity Slow Fast Fastest

11 Myosin-actin cross-bridge kinetics Myosin detachment time (t off ) Myosin attachment time (t on ) Myosin on F XB Myosin off t Isometric force (F Iso ): on F Iso = N F t XB on + t off Velocity 1 t on Force (F Iso ): F XB = 2 F XB Velocity: 1.0 ML/s Myosin head number (N) Time Maximum tension (mn/mm 2 ) MHC IIA (Fast) MHC I (Slow) Young Older Immobilized Older D Antona et al. (2003) J Physiol

12 Myosin-actin cross-bridge kinetics Myosin detachment time (t off ) Myosin attachment time (t on ) Myosin on F XB Myosin off t Isometric force (F Iso ): on F Iso = N F t XB on + t off Velocity 1 t on Young N by 20% t on by 25% Force (F Iso ): F XB = 2 F XB F XB = 1.6 F XB F XB = 2.5 F XB Velocity: Myosin head number (N) ML/s 1.0 ML/s 0.80 ML/s Time Hypothesis: Aging decreases single fiber force Aging decreases single fiber velocity

13 Myosin on Myosin off Myosin-actin cross-bridge kinetics Myosin detachment time (t off ) Rate of force production Myosin attachment time (t on ) F XB MHC I (Slow) Age Age by Sex = 0.08 *** = Young = Older Myosin strongly bound Forward Post-power stroke Pre-power stroke Reverse MHC IIA (Fast) Age Age by Sex *** Myosin weakly bound Age or Age by Sex = Significant age or age by sex difference (P<0.05) Asterisks indicate significant difference (*** = P<0.001) between young and older females Male Female

14 Molecular level Age-related changes in muscle function Rate of force production Myosin attachment time Slower cross-bridge kinetics with age Single fiber level Isometric tension Contractile velocity (Predicted) Whole muscle level Isometric torque Isokinetic power Power = Force x Velocity Whole body level Physical activity Functional performance (peak O 2 consumption)

15 Preliminary findings from knee osteoarthritis + training study MHC I Power (mn/mm 2 x ML/s) Female, Pre Male, Pre Tension (mn/mm 2 )

16 Preliminary findings from knee osteoarthritis + training study Power (mn/mm 2 x ML/s) Maximum Tension (mn/mm 2 ) Female, Pre Female, Post Male Male, Pre Tension (mn/mm 2 ) Sex Train by Sex Female MHC I Male, Post Myosin attachment time or t on (ms) B (mn/mm 2 ) = Pre-resistance training = Post-resistance training Male Train by Sex Train by Sex Female

17 Previously measured Future Directions PT = Power Training, RT = Resistance Training Males Females Molecular to whole muscle function Aging Aging + Disease RT Aerobic PT RT PT Aerobic Aging Aging + Disease PT Aerobic RT RT and PT RT Aerobic Time Time This is a novel approach in that exercise programs would be developed for clinical applications by correcting the fundamental molecular and cellular pathology of aging and disease.

18 Acknowledgments Volunteers CRC Staff Philip Ades Michael Toth Brad Palmer David Maughan Jim Vigoreaux Joan Braddock Damien Callahan Rich Lachapelle Michael Previs Bertrand Tanner Kimberly Ward Katie Bedard Nicholas Bedrin* James Berking* Hilary Kulakowski Mariel Maling Andrew Sweeney* Juliana Yellin

19 Single skinned fiber muscle mechanics (sinusoidal analysis) Isolate and skin single muscle fiber. Mount fiber with t-clips to force transducer and servo motor. Measure elastic modulus, viscous modulus, and work output by oscillating the muscle from to 200 Hz (sinusoidal analysis) Expose fiber to exposed to different Ca 2+ conditions Use sinusoidal analysis and curve fitting parameters to calculate a myosin attachment time (t on ) Palmer et al. (2007) Biophys J

20 Curve fitting parameters for sinusoidal analysis data Viscous Modulus (kn/m 2 ) Y ( ω) = A( iω) k iω iω B + C 2π b + iω 2π c + iω B b 200 Hz 0.5 Hz A c (2πc) -1 is equivalent to myosin attachment time (t on ) Palmer et al. (2007) Biophys J kπ / 2 C Elastic Modulus (kn/m 2 )