Temporal disruption of neuromuscular communication and muscle atrophy following noninvasive ACL injury in rats

Emily R. Hunt, Steven M. Davi, Cassandra N. Parise, Kaleigh Clark, Douglas W. Van Pelt, Amy L. Confides, Kimberly A. Buckholts, Cale A. Jacobs, Christian Lattermann, Esther E. Dupont-Versteegden, Timothy A. Butterfield, Lindsey K. Lepley

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Many patients with anterior cruciate ligament (ACL) injuries have persistent quadriceps muscle atrophy, even after considerable time in rehabilitation. Understanding the factors that regulate muscle mass, and the time course of atrophic events, is important for identifying therapeutic interventions. With a noninvasive animal model of ACL injury, a longitudinal study was performed to elucidate key parameters underlying quadriceps muscle atrophy. Male Long-Evans rats were euthanized at 6, 12, 24, or 48 h or 1, 2, or 4 wk after ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle size was determined by wet weight and fiber cross-sectional area (CSA). Evidence of disrupted neuromuscular communication was assessed via the expression of neural cell adhesion molecule (NCAM) and genes associated with denervation and neuromuscular junction instability. Abundance of muscle RING-finger protein-1 (MuRF-1), muscle atrophy F-box (MAFbx), and 45 s pre-rRNA along with 20S proteasome activity were determined to investigate mechanisms related to muscle atrophy. Finally, muscle damage-related parameters were assessed by measuring IgG permeability, centronucleation, CD68 mRNA, and satellite cell abundance. When compared with controls, we observed a greater percentage of NCAM-positive fibers at 6 h postinjury, followed by higher MAFbx abundance 48 h postinjury, and higher 20S proteasome activity at 1 wk postinjury. A loss of muscle wet weight, smaller fiber CSA, and the elevated expression of run-related transcription factor 1 (Runx1) were also observed at the 1 wk postinjury timepoint relative to controls. There also were no differences observed in any damage markers. These results indicate that alterations in neuromuscular communication precede the upregulation of atrophic factors that regulate quadriceps muscle mass early after noninvasive ACL injury.

Original languageEnglish
Pages (from-to)46-57
Number of pages12
JournalJournal of Applied Physiology
Issue number1
StatePublished - Jan 2022

Bibliographical note

Funding Information:
This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant K01AR071503 (to L. K. Lepley).

Publisher Copyright:
© 2022 the American Physiological Society.


  • Anterior cruciate ligament
  • Muscle atrophy
  • Neuromuscular communication
  • Quadriceps
  • Time course

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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