|
| Status |
Public on Jan 11, 2023 |
| Title |
Depressed protein synthesis and anabolic signaling potentiate ACL tear resultant quadriceps atrophy I |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Background: An anterior cruciate ligament tear (ACLT) leads to protracted quadriceps weakness and atrophy. Protein turnover largely dictates muscle size and is highly responsive to injury and loading. Regulation of the molecular protein synthetic machinery within the quadriceps following ACLT has largely been unexplored, limiting the development of targeted therapies. Purpose: To define the effect of ACLT on 1) activation of protein synthetic and catabolic signaling within quadriceps biopsies from human participants, and 2) the time course of alterations to protein synthesis and its molecular regulation in a mouse model of ACL injury. Study Design: Descriptive laboratory studyMethods: Muscle biopsy specimens were obtained from the ACL-injured and non-injured vastus lateralis of young adults following 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, 1, 3, or 7 days post-injury with puromycin (0.04µmol/g) injected 30 minutes before tissue collection. Muscle fiber size and expression and phosphorylation of protein anabolic signaling proteins and E3 ubiquitin ligases were assessed at the protein and transcript level. Relative protein synthesis was measured by puromycin incorporation in mice.Results: Human quadriceps showed reduced phosphorylation of ribosomal protein S6 (-41%) in the ACL-injured limb (p<0.05), in addition to elevated phosphorylation of eukaryotic initiation factor 2α (+98%, p<0.05), indicative of depressed protein anabolic signaling in the injured limb. No differences in E3 ubiquitin ligase expression were noted (p>0.05). Protein synthesis was lower at 1 and 3 days post-ACLT in mice (p<0.05 vs. control limb). Conclusions: 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 prior to the onset of significant atrophy, underscoring the need for early intervention. Clinical Relevance: These findings suggest blunted protein anabolism as opposed to increased catabolism likely mediates the quadriceps atrophy that occurs following ACL injury. Thus, future interventions should aim to restore muscle protein anabolism rapidly following the initial injury.
|
| |
|
| Overall design |
Comparative gene expression was assessed in human quadricep tissue in non-ACL injured limbs and ACL-injured limbs pre reconstruction surgery
|
| |
|
| Contributor(s) |
Keeble AR, Brightwell CR, Latham CM, Thomas NT, Mobley CB, Murach KA, Johnson DL, Noehren B, Fry CS |
| Citation(s) |
- Keeble AR, Brightwell CR, Latham CM, Thomas NT et al. Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear-Resultant Quadriceps Atrophy. Am J Sports Med 2023 Jan;51(1):81-96. PMID: 36475881
- Wen Y, Latham CM, Moore AN, Thomas NT et al. Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction. JCI Insight 2023 Dec 8;8(23). PMID: 37856482
|
| <button class="button" id="geo2r_button">Analyze with GEO2R</button> <button class="button" id="download_button">Download RNA-seq counts</button> |
| Submission date |
Aug 19, 2022 |
| Last update date |
Jan 29, 2024 |
| Contact name |
Alexander Romano Keeble |
| E-mail(s) |
arke243@uky.edu
|
| Phone |
2175861693
|
| Organization name |
University of Kentucky
|
| Street address |
900 S Limestone st
|
| City |
Lexington |
| State/province |
KY |
| ZIP/Postal code |
40536 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
|
|
