|
1
|
Edouard P, Reurink G, Mackey AL, Lieber RL, Pizzari T, Järvinen TAH, Gronwald T, Hollander K. Traumatic muscle injury. Nat Rev Dis Primers 2023; 9:56. [PMID: 37857686 DOI: 10.1038/s41572-023-00469-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/22/2023] [Indexed: 10/21/2023]
Abstract
Traumatic muscle injury represents a collection of skeletal muscle pathologies caused by trauma to the muscle tissue and is defined as damage to the muscle tissue that can result in a functional deficit. Traumatic muscle injury can affect people across the lifespan and can result from high stresses and strains to skeletal muscle tissue, often due to muscle activation while the muscle is lengthening, resulting in indirect and non-contact muscle injuries (strains or ruptures), or from external impact, resulting in direct muscle injuries (contusion or laceration). At a microscopic level, muscle fibres can repair focal damage but must be completely regenerated after full myofibre necrosis. The diagnosis of muscle injury is based on patient history and physical examination. Imaging may be indicated to eliminate differential diagnoses. The management of muscle injury has changed within the past 5 years from initial rest, immobilization and (over)protection to early activation and progressive loading using an active approach. One challenge of muscle injury management is that numerous medical treatment options, such as medications and injections, are often used or proposed to try to accelerate muscle recovery despite very limited efficacy evidence. Another challenge is the prevention of muscle injury owing to the multifactorial and complex nature of this injury.
Collapse
Affiliation(s)
- Pascal Edouard
- Université Jean Monnet, Lyon 1, Université Savoie Mont-Blanc, Inter-university Laboratory of Human Movement Biology, Saint-Etienne, France.
- Department of Clinical and Exercise Physiology, Sports Medicine Unit, University Hospital of Saint-Etienne, Faculty of Medicine, Saint-Etienne, France.
| | - Gustaaf Reurink
- Department of Orthopedic Surgery and Sports Medicine, Academic Medical Center, University of Amsterdam, Amsterdam Movement Sciences, Amsterdam, Netherlands
- Academic Center for Evidence-based Sports Medicine (ACES), Academic Medical Center, Amsterdam, Netherlands
- The Sports Physicians Group, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
| | - Abigail L Mackey
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark
- Center for Healthy Aging, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Richard L Lieber
- Shirley Ryan AbilityLab, Chicago, IL, USA
- Departments of Physical Medicine and Rehabilitation and Biomedical Engineering, Northwestern University, Chicago, IL, USA
- Hines VA Medical Center, Maywood, IL, USA
| | - Tania Pizzari
- La Trobe Sport and Exercise Medicine Research Centre, La Trobe University, Melbourne, Victoria, Australia
| | - Tero A H Järvinen
- Tampere University and Tampere University Hospital, Tampere, Finland
| | - Thomas Gronwald
- Institute of Interdisciplinary Exercise Science and Sports Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Karsten Hollander
- Institute of Interdisciplinary Exercise Science and Sports Medicine, MSH Medical School Hamburg, Hamburg, Germany
| |
Collapse
|
|
2
|
Luo Z, Qi B, Sun Y, Chen Y, Lin J, Qin H, Wang N, Shi R, Shang X, Chen S, Chen J. Engineering Bioactive M2 Macrophage-Polarized, Anti-inflammatory, miRNA-Based Liposomes for Functional Muscle Repair: From Exosomal Mechanisms to Biomaterials. SMALL 2022; 18:e2201957. [PMID: 35802903 DOI: 10.1002/smll.202201957] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/03/2022] [Indexed: 02/05/2023]
Abstract
Severe inflammation and myogenic differentiation disorder are the major obstacles to skeletal muscle healing after injury. MicroRNAs (miRNAs) play an important role as regulatory molecules during the process of muscle healing, but the detailed mechanism of miRNA-mediated intercellular communication between myoblasts and macrophages remains unclear. Here, it is reported that myoblasts secrete miRNAs-enriched exosomes in the inflammatory environment, through which miR-224 is transferred into macrophages to inhibit M2 polarization. Further data demonstrate that WNT-9a may be a direct target of miR-224 for macrophage polarization. In turn, the secretome of M1 macrophages impairs myogenic differentiation and promotes proliferation. Single-cell integration analysis suggests that the elevation of exosome-derived miR-224 is caused by the activation of the key factor E2F1 in myoblasts and demonstrates the RB/E2F1/miR-224/WNT-9a axis. In vivo results show that treatment with antagomir-224 or liposomes containing miR-224 inhibitors suppresses fibrosis and improves muscle recovery. These findings indicate the importance of the crosstalk between myoblasts and macrophages via miRNA-containing exosomes in the regulation of macrophage polarization and myogenic differentiation/proliferation during muscle healing. This study provides a strategy for treating muscle injury through designing an M2 polarization-enabling anti-inflammatory and miRNA-based bioactive material.
Collapse
Affiliation(s)
- Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Beijie Qi
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Yaying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Yisheng Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Jinrong Lin
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Haocheng Qin
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, 200433, P. R. China
| | - Ning Wang
- Department of Ophthalmology, Shanghai 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Runjie Shi
- Department of Otorhinolaryngology Head and Neck Surgery, Shanghai ninth people's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Xiliang Shang
- Department of Ophthalmology, Shanghai 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Jiwu Chen
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, P. R. China
| |
Collapse
|
|
3
|
Luo ZW, Sun YY, Lin JR, Qi BJ, Chen JW. Exosomes derived from inflammatory myoblasts promote M1 polarization and break the balance of myoblast proliferation/differentiation. World J Stem Cells 2021; 13:1762-1782. [PMID: 34909122 PMCID: PMC8641021 DOI: 10.4252/wjsc.v13.i11.1762] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/28/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute muscle injuries are one of the most common injuries in sports. Severely injured muscles are prone to re-injury due to fibrotic scar formation caused by prolonged inflammation. How to regulate inflammation and suppress fibrosis is the focus of promoting muscle healing. Recent studies have found that myoblasts and macrophages play important roles in the inflammatory phase following muscle injury; however, the crosstalk between these two types of cells in the inflammatory environment, particularly the exosome-related mechanisms, had not been well studied.
AIM To evaluate the effects of exosomes from inflammatory C2C12 myoblasts (IF-C2C12-Exos) on macrophage polarization and myoblast proliferation/differentiation.
METHODS A model of inflammation was established in vitro by lipopolysaccharide stimulation of myoblasts. C2C12-Exos were isolated and purified from the supernatant of myoblasts by gradient centrifugation. Multiple methods were used to identify the exosomes. Gradient concentrations of IF-C2C12-Exos were added to normal macrophages and myoblasts. PKH67 fluorescence tracing was used to identify the interaction between exosomes and cells. Microscopic morphology, Giemsa stain, and immunofluorescence were carried out for histological analysis. Additionally, ELISA assays, flow cytometry, and western blot were conducted to analyze molecular changes. Moreover, myogenic proliferation was assessed by the BrdU test, scratch assay, and CCK-8 assay.
RESULTS We found that the PKH-67-marked C2C12-Exos can be endocytosed by both macrophages and myoblasts. IF-C2C12-Exos induced M1 macrophage polarization and suppressed the M2 phenotype in vitro. In addition, these exosomes also stimulated the inflammatory reactions of macrophages. Furthermore, we demonstrated that IF-C2C12-Exos disrupted the balance of myoblast proliferation/differentiation, leading to enhanced proliferation and suppressed fibrogenic/myogenic differentiation.
CONCLUSION IF-C2C12-Exos can induce M1 polarization, resulting in a sustained and aggravated inflammatory environment that impairs myoblast differentiation, and leads to enhanced myogenic proliferation. These results demonstrate why prolonged inflammation occurs after acute muscle injury and provide a new target for the regulation of muscle regeneration.
Collapse
Affiliation(s)
- Zhi-Wen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ya-Ying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jin-Rong Lin
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Bei-Jie Qi
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ji-Wu Chen
- Department of Sports Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
4
|
Bayer ML, Hoegberget-Kalisz M, Svensson RB, Hjortshoej MH, Olesen JL, Nybing JD, Boesen M, Magnusson SP, Kjaer M. Chronic Sequelae After Muscle Strain Injuries: Influence of Heavy Resistance Training on Functional and Structural Characteristics in a Randomized Controlled Trial. Am J Sports Med 2021; 49:2783-2794. [PMID: 34264782 DOI: 10.1177/03635465211026623] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Muscle strain injury leads to a high risk of recurrent injury in sports and can cause long-term symptoms such as weakness and pain. Scar tissue formation after strain injuries has been described, yet what ultrastructural changes might occur in the chronic phase of this injury have not. It is also unknown if persistent symptoms and morphological abnormalities of the tissue can be mitigated by strength training. PURPOSE To investigate if heavy resistance training improves symptoms and structural abnormalities after strain injuries. STUDY DESIGN Randomized controlled trial; Level of evidence, 1. METHODS A total of 30 participants with long-term weakness and/or pain after a strain injury of the thigh or calf muscles were randomized to eccentric heavy resistance training of the injured region or control exercises of the back and abdominal muscle. Isokinetic (hamstring) or isometric (calf) muscle strength was determined, muscle cross-sectional area measured, and pain and function evaluated. Scar tissue ultrastructure was determined from biopsy specimens taken from the injured area before and after the training intervention. RESULTS Heavy resistance training over 3 months improved pain and function, normalized muscle strength deficits, and increased muscle cross-sectional area in the previously injured region. No systematic effect of training was found upon pathologic infiltration of fat and blood vessels into the previously injured area. Control exercises had no effect on strength, cross-sectional area, or scar tissue but a positive effect on patient-related outcome measures, such as pain and functional scores. CONCLUSION Short-term strength training can improve sequelae symptoms and optimize muscle function even many years after a strain injury, but it does not seem to influence the overall structural abnormalities of the area with scar tissue. REGISTRATION NCT02152098 (ClinicalTrials.gov identifier).
Collapse
Affiliation(s)
- Monika L Bayer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Maren Hoegberget-Kalisz
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Rene B Svensson
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel H Hjortshoej
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Physical and Occupational Therapy, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Jens L Olesen
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Research Unit for General Practice in Aalborg, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Janus D Nybing
- Department of Radiology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Mikael Boesen
- Department of Radiology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - S Peter Magnusson
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Physical and Occupational Therapy, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
5
|
Jakobsen JR, Krogsgaard MR. The Myotendinous Junction-A Vulnerable Companion in Sports. A Narrative Review. Front Physiol 2021; 12:635561. [PMID: 33841171 PMCID: PMC8032995 DOI: 10.3389/fphys.2021.635561] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/15/2021] [Indexed: 01/17/2023] Open
Abstract
The incidence of strain injuries continues to be high in many popular sports, especially hamstring strain injuries in football, despite a documented important effect of eccentric exercise to prevent strains. Studies investigating the anatomical properties of these injuries in humans are sparse. The majority of strains are seen at the interface between muscle fibers and tendon: the myotendinous junction (MTJ). It has a unique morphology with a highly folded muscle membrane filled with invaginations of collagen fibrils from the tendon, establishing an increased area of force transmission between muscle and tendon. There is a very high rate of remodeling of the muscle cells approaching the MTJ, but little is known about how the tissue adapts to exercise and which structural changes heavy eccentric exercise may introduce. This review summarizes the current knowledge about the anatomy, composition and adaptability of the MTJ, and discusses reasons why strain injuries can be prevented by eccentric exercise.
Collapse
Affiliation(s)
- Jens Rithamer Jakobsen
- Section of Sports Traumatology, M51, A Part of IOC Research Center, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | | |
Collapse
|