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Older mice show decreased regeneration of neuromuscular junctions following lengthening contraction-induced injury

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Abstract

Progressive muscle atrophy and loss of muscle strength associated with old age have been well documented. Although age-associated impairments in skeletal muscle regeneration following injury have been demonstrated, less is known about whether aging impacts the regenerative response of neuromuscular junctions (NMJ) following contraction-induced injury. Reduced ability of NMJs to regenerate could lead to increased numbers of denervated muscle fibers and therefore play a contributing role to age-related sarcopenia. To investigate the relationship between age and NMJ regeneration following injury, extensor digitorum longus (EDL) muscles of middle-aged (18–19 months) and old mice (27–28 months) were subjected to a protocol of lengthening contractions (LC) that resulted in an acute force deficit of ~55% as well as functional and histological evidence of a similar magnitude of injury 3 days post LCs that was not different between age groups. After 28 days, the architecture and innervation of the NMJs were evaluated. The numbers of fragmented endplates increased and of fully innervated NMJs decreased post-injury for the muscle of both middle-aged and old mice and for contralateral uninjured muscles of old compared with uninjured muscles of middle-aged controls. Thus, the diminished ability of the skeletal muscle of old mice to recover following injury may be due in part to an age-related decrease in the ability to regenerate NMJs in injured muscles. The impaired ability to regenerate NMJs may be a triggering factor for degenerative changes at the NMJ contributing to muscle fiber weakness and loss in old age.

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Funding

The authors acknowledge the generous funding support from the National Institute on Aging (AG051442) for this work.

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Thomas A. Paul, Peter C. Macpherson, Tara L. Janetzke, Carol S. Davis & Susan V. Brooks

  2. Department of Biomedical Engineering, University of Michigan, 2029 Biomedical Sciences Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    Thomas A. Paul & Susan V. Brooks

  3. MRC-Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Life Course and Ageing Science, University of Liverpool, Liverpool, UK

    Malcolm J. Jackson & Anne McArdle

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  1. Thomas A. Paul
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Contributions

All authors contributed to the study conception and design. Data collection was performed by Thomas Paul, Peter Macpherson, Tara Janetzke, and Carol Davis. Analysis was performed by Thomas Paul and Peter Macpherson. The first draft of the manuscript was written by Thomas Paul, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Susan V. Brooks.

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Paul, T.A., Macpherson, P.C., Janetzke, T.L. et al. Older mice show decreased regeneration of neuromuscular junctions following lengthening contraction-induced injury. GeroScience 45, 1899–1912 (2023). https://doi.org/10.1007/s11357-023-00774-w

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