Abstract
Background: Anterior cruciate ligament (ACL) tear (ACLT) leads to protracted quadriceps muscle atrophy. Protein turnover largely dictates muscle size and is highly responsive to injury and loading. Regulation of quadriceps molecular protein synthetic machinery after ACLT has largely been unexplored, limiting development of targeted therapies. Purpose: To define the effect of ACLT on (1) the activation of protein synthetic and catabolic signaling within quadriceps biopsy specimens from human participants and (2) the time course of alterations to protein synthesis and its molecular regulation in a mouse ACL injury model. Study Design: Descriptive laboratory study. Methods: Muscle biopsy specimens were obtained from the ACL-injured and noninjured vastus lateralis of young adult humans after an overnight fast (N = 21; mean ± SD, 19 ± 5 years). Mice had their limbs assigned to ACLT or control, and whole quadriceps were collected 6 hours or 1, 3, or 7 days after injury with puromycin injected before tissue collection for assessment of relative protein synthesis. Muscle fiber size and expression and phosphorylation of protein anabolic and catabolic signaling proteins were assessed at the protein and transcript levels (RNA sequencing). Results: Human quadriceps showed reduced phosphorylation of ribosomal protein S6 (–41%) in the ACL-injured limb (P =.008), in addition to elevated phosphorylation of eukaryotic initiation factor 2α (+98%; P =.006), indicative of depressed protein anabolic signaling in the injured limb. No differences in E3 ubiquitin ligase expression were noted. Protein synthesis was lower at 1 day (P =.01 vs control limb) and 3 days (P =.002 vs control limb) after ACLT in mice. Pathway analyses revealed shared molecular alterations between human and mouse quadriceps after ACLT. Conclusion: (1) Global protein synthesis and anabolic signaling deficits occur in the quadriceps in response to ACL injury, without notable changes in measured markers of muscle protein catabolism. (2) Importantly, these deficits occur before the onset of significant atrophy, underscoring the need for early intervention. Clinical Relevance: These findings suggest that blunted protein anabolism as opposed to increased catabolism likely mediates quadriceps atrophy after ACL injury. Thus, future interventions should aim to restore muscle protein anabolism rapidly after ACLT.
Original language | English |
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Pages (from-to) | 81-96 |
Number of pages | 16 |
Journal | American Journal of Sports Medicine |
Volume | 51 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2023 |
Bibliographical note
Funding Information:One or more of the authors has declared the following potential conflict of interest or source of funding: Research reported in this publication was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) under award R01 AR072061 to C.S.F. D.L.J. has received travel expenses from Linvatec; compensation for services other than consulting, royalty or license, and consulting fees from Smith & Nephew; and consulting fees from Xiros Inc. The myosin heavy chain fiber type 2a (SC-71) and 2b (BF-F3) antibodies were developed by S. Schiaffino and obtained from the Developmental Studies Hybridoma Bank, created by the National Institute of Child Health and Human Development of the NIH and maintained at the Department of Biology, University of Iowa. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.
Publisher Copyright:
© 2022 The Author(s).
Keywords
- E3 ubiquitin ligase
- anterior cruciate ligament
- protein metabolism
- skeletal muscle
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
- Physical Therapy, Sports Therapy and Rehabilitation