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Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline

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A Correction to this article was published on 13 October 2021

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Abstract

Pathological age-related loss of skeletal muscle strength and mass contribute to impaired physical function in older adults. Factors that promote the development of these conditions remain incompletely understood, impeding development of effective and specific diagnostic and therapeutic approaches. Inconclusive evidence across species suggests disruption of action potential signal transmission at the neuromuscular junction (NMJ), the crucial connection between the nervous and muscular systems, as a possible contributor to age-related muscle dysfunction. Here we investigated age-related loss of NMJ function using clinically relevant, electrophysiological measures (single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS)) in aged (26 months) versus young (6 months) F344 rats. Measures of muscle function (e.g., grip strength, peak plantarflexion contractility torque) and mass were assessed for correlations with physiological measures (e.g., indices of NMJ transmission). Other outcomes also included plantarflexion muscle contractility tetanic torque fade during 1-s trains of stimulation as well as gastrocnemius motor unit size and number. Profiling NMJ function in aged rats identified significant declines in NMJ transmission stability and reliability. Further, NMJ deficits were tightly correlated with hindlimb grip strength, gastrocnemius muscle weight, loss of peak contractility torque, degree of tetanic fade, and motor unit loss. Thus, these findings provide direct evidence for NMJ dysfunction as a potential mechanism of age-related muscle dysfunction pathogenesis and severity. These findings also suggest that NMJ transmission modulation may serve as a target for therapeutic development for age-related loss of physical function.

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Data availability

Data is available upon request from the corresponding author.

Change history

Abbreviations

CMAP:

Compound muscle action potential

MUNE:

Motor unit number estimation

NMJ:

Neuromuscular junction

RNS:

Repetitive nerve stimulation

SFAP:

Single-fiber action potential

SFEMG:

Single-fiber electromyography

SMUP:

Single motor unit potential

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Funding

WDA was funded by the National Institutes of Health (NIH) R56AG055795 (NIA). BCC was funded by NIH R01AG044424 (NIA). JMS is supported by the National Institute of Disability, Independent Living and Rehabilitation Research Grant 90SI5020, NIH R01 NS118200-01 (NINDS), the European Union Era Net – Neuron Program, SILENCE Grant 01EW170A, the Craig H Neilsen Foundation Grant 596764, the Wings for Life Spinal Cord Research Foundation, and the William E. Hunt and Charlotte M. Curtis endowment. JMS is also a Discovery Theme Initiative Scholar (Chronic Brain Injury) of The Ohio State University. MRR was funded by NIH R01 AR074985

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  1. Division of Neuromuscular Diseases, Department of Neurology, The Ohio State University Wexner Medical Center, 1060 Carmack Road, Room 207, Columbus, OH, 43210, USA

    Carlos J. Padilla, Markus E. Harrigan, Hallie Harris, Jan M. Schwab & W. David Arnold

  2. Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab

  3. Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab & W. David Arnold

  4. Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab

  5. The Neurological Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab & W. David Arnold

  6. Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab & W. David Arnold

  7. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Seward B. Rutkove

  8. Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH, 45435, USA

    Mark M. Rich

  9. Department of Biomedical Sciences, Ohio Musculoskeletal and Neurological Institute, Athens, OH, 45701, USA

    Brian C. Clark

  10. Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    W. David Arnold

Authors
  1. Carlos J. Padilla
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  2. Markus E. Harrigan
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  3. Hallie Harris
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  4. Jan M. Schwab
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  5. Seward B. Rutkove
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  6. Mark M. Rich
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  7. Brian C. Clark
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  8. W. David Arnold
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Contributions

Study Design: CP, MH, HH, SR, BC, and WA. Data acquisition: CP, MH, HH, WA. Data analyses and interpretation: CP, MH, JS, SR, MR, BC, WA. Draft of the manuscript: CP, BC, WA. Editing of manuscript: CP, MH, HH, JS, SR, MR, BC, WA. Acquisition of funding: JS, MR, BC, WA.

Corresponding author

Correspondence to W. David Arnold.

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Ethics approval

All procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee of The Ohio State University.

Competing interests

SBR has equity in, and serves a consultant and scientific advisor to, Myolex Inc., a company that designs impedance devices for clinical and research use; he is also a member of the company’s Board of Directors. The company also has an option to license patented impedance technology for which SBR is named as an inventor. In the past 3 years, BCC and WDA have received research funding from NMD Pharma for aging muscle research; BCC has received funding from Astellas Pharma Global Development, Inc. for aging muscle research; and BCC has served as a consultant to Regeneron Pharmaceuticals for topics pertinent to aging muscle research.

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Padilla, C.J., Harrigan, M.E., Harris, H. et al. Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline. GeroScience 43, 1265–1281 (2021). https://doi.org/10.1007/s11357-021-00369-3

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  • DOI: https://doi.org/10.1007/s11357-021-00369-3

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