Structural determinants of quadriceps atrophy following ACL injury: Evidence for fibre atrophy without fibre loss or overt peripheral denervation.

Overview

1. School of Kinesiology University of Michigan Ann Arbor Michigan USA
2. Michigan State University College of Osteopathic Medicine East Lansing Michigan USA
3. Saint Louis University School of Medicine St. Louis Missouri USA
4. Department of Molecular and Integrative Physiology University of Michigan Ann Arbor Michigan USA

Abstract

Abstract: Quadriceps atrophy is a well‐established consequence of anterior cruciate ligament (ACL) injury, yet the mechanisms driving this process remain poorly characterized. Specifically, it is unclear whether atrophy reflects decreases in fibre cross‐sectional area (CSA) or fibre number, and whether the neural inhibition accompanying ACL injury extends to peripheral neuromuscular junctions (NMJs). Using a rat model of non‐invasive ACL injury and whole‐muscle histological analysis, we quantified changes in vastus lateralis fibre CSA, fibre number, fibre‐type distribution, and NMJ integrity and function at early post‐injury timepoints. By 7 days post‐injury, fibre CSA was significantly reduced in both sexes across all Type II subtypes, with deficits persisting at 14 days. Total fibre number was maintained, demonstrating that whole‐muscle atrophy is driven primarily by reductions in fibre CSA rather than fibre loss. At 3 days post‐injury, no significant difference in NMJ innervation and compound muscle action potential amplitude were observed, suggesting that early atrophy is not preceded by peripheral denervation. Reductions in electromyographic amplitude and stance duration during treadmill walking indicated decreased muscle activation and limb loading following injury. Shifts in fibre‐type distribution to IIb were also observed. This work clarifies the structural basis of early quadriceps atrophy following ACL injury, demonstrating that quadriceps atrophy is likely not preceded by peripheral denervation and is characterized primarily by reductions in fibre CSA. These findings support rehabilitation strategies that target fibre growth, but the persistent nature of quadriceps atrophy in patients suggests that current approaches may be insufficient and require further optimization.

Key points: Anterior cruciate ligament (ACL) injury results in persistent quadriceps atrophy, yet whether deficits in whole‐muscle size result from reductions in fibre cross‐sectional area or number, and whether the integrity of neuromuscular junctions is impaired, remains unclear. Using a rat model of ACL injury and whole‐muscle histology, we demonstrate that quadriceps atrophy is driven by decreased fibre cross‐sectional area, not fibre loss, and that this affects all Type II subtypes. Quadriceps neuromuscular junctions remained structurally and functionally intact, demonstrating that early quadriceps atrophy is not preceded by denervation. Shifts in fibre‐type composition toward a more glycolytic phenotype were observed, consistent with patterns reported in models of muscle unloading and disuse. By identifying fibre‐level atrophy without fibre loss, these findings highlight a key therapeutic target and support strategies that target fibre growth to address the persistent atrophy that plagues ACL‐injured patients.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data availability statement

The data that support the findings of this study are archived and available upon reasonable request to the corresponding author. Raw immunofluorescence images used for fibre typing, generating composite erosion files, and the associated Python processing pipeline are archived and available upon request. Similarly, raw NMJ morphology data, CMAP recordings, and gait/stance duration measurements, along with their corresponding processing scripts, are archived and available upon request. No data from this study have been deposited in a public repository.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Wiley

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 3 keywords, 10 MeSH terms, 1 funder, 70 references.

Cite

This paper

Stoneback, L., Buchanan, B., Hussein, H. W., Ali, D., Naaz, S., Gustafson, K., Vaikutis, L., Damouni, L., Macpherson, P. C. D., & Lepley, L. K. (2026). Structural determinants of quadriceps atrophy following ACL injury: Evidence for fibre atrophy without fibre loss or overt peripheral denervation. The Journal of physiology, 604(17), 7287-7312. https://doi.org/10.1113/jp291436

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