Muscle Injuries: Regeneration Strategies

Original Editor - Lucinda hampton

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Introduction[edit | edit source]

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In humans, up to half of body mass is made up of skeletal muscle, which plays a key role in locomotion, posture, and breathing. Although skeletal muscles can overcome minor tears and bruising without intervention, major injuries commonly caused by motor vehicle accidents, other traumas, or nerve damage can lead to extensive scarring, fibrous tissue, and loss of muscle function[1]. Up to 20% loss of muscle mass can be compensated by the high adaptability and regenerative potential of skeletal muscle. Beyond this threshold functional impairment is inevitable and can lead to severe disability as well as cosmetic deformities, which is why therapeutic options are in urgent demand for these patients

Patients with a need for these skeletal muscle regenerative procedures include those with:

  • Acute muscle tissue loss include: high-energy traffic accidents; blast trauma; combat injuries; surgical procedures; orthopedic situations (e.g., after compartment syndrome or tumor resection).
  • Sports injuries: Approximately 35–55% of sport injuries involve muscle damage at the myofiber level. Those injuries that involve 20% or more of muscle loss of the respective muscle mass need reconstructive surgical procedures, that could be potentially avoided.
  • Progressive muscle loss resulting from metabolic disorders or inherited genetic diseases eg Duchenne muscular dystrophy, Motor Neurone Disease.
  • Muscle atrophy as a consequence of eg peripheral nerve injuries, chronic kidney disease, diabetes, and heart failure[2].[3]

Strategies to improve Muscle Regeneration and Repair[edit | edit source]

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After a trauma, skeletal muscles have the capacity to regenerate and repair in a complex and well-coordinated response.  

  • This process required the presence of diverse cell populations, up and down-regulation of various gene expressions and participation of multiples growth factors.  
  • Strategies to improve muscle regeneration and repair, including the combination of stem cells, growth factors and biological scaffolds, are showing promising results in animal models.[3] 

Growth factors[edit | edit source]

Growth factors play a variety of roles in the different stages of muscle regeneration. These biologically active molecules, synthetized by the injured tissue or by other cell types present at the inflammatory site, are release in the extracellular space and modulate the regenerative response.[3]

  • Insulin like growth factor-1 (IGF-I) appears to be of particular importance for the muscle regeneration process. IGF-I stimulates myoblasts proliferation and differentiation and is implicated in the regulation of muscle growth[4]

Stem cells[edit | edit source]

Image:Human Mesenchymal Stem Cell interacting with 3D hydrogel.

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Transplantation of satellite cell-derived myoblasts has long been explored as a promising approach for treatment of skeletal muscle disorders.

  • Stem cell therapy (e.g., umbilical cord blood stem cell transplantation) showed positive results for treating Duchenne muscular dystrophy. After application of stem cells, an increase of dystrophin positive muscular fibers was found. However clinical trials, in which allogeneic normal human myoblasts were injected intramuscularly several times in dystrophic young boys muscles, have not been successful[3][2]
  • Exciting and innovative research related to the potential of many types of stem cells for slowing MS disease activity and for repairing damage to the nervous system is in progress. Although cell based therapy has generated a great deal of interest and holds promise, the field is in its infancy and much more research is needed before cell based therapies become a MS treatment option.[5]
  • Stem cell therapy could potentially be a novel therapeutic intervention for sarcopenia alleviation owing to its regenerative capabilities and its ability to produce anti-inflammatory cytokines that in turn change the microenvironment into one that promotes reinnervation and regeneration. Numerous studies for sarcopenia has looked into the effects of exercise, nutraceutical and protein supplements in sarcopenia alleviation but none has looked at the effects of exercise along with the concurrent use of stem cell secretome, which could be a novel antisarcopenia approach that could potentially provide an even better outcome than the other classical approach[6].
  • Amniotic fluid mesenchymal stem cells(AFS) in combination with hyperbaric oxygen augment peripheral nerve regeneration[7].

Macrophage Manipulation[edit | edit source]

Full restoration of skeletal muscle structure and function after traumatic injury requires several different cell types and numerous molecules working together to efficiently control the damaged tissue through each phase of healing. Macrophages are known to play essential roles in each phase of efficient muscle regeneration. Soon after muscle injury, the number of M1 macrophages rapidly increases in the injured area, and approximately 2 days later, this population is replaced by M2 macrophages.

  • M1 macrophages reduce collagen production via fibroblasts and stimulate myoblast proliferation
  • M2 macrophages increase collagen production and promote myoblast differentiation and fusion to form myofibers
  • The order of M1 and M2 macrophage production and the duration of the activity of each subtype in the injured area are directly related to the extent of fibrogenesis and myogenesis, and any significant changes in these processes can result in more fibrosis and less regenerated muscle or vice versa.

A recent study shows that the temporal increase in the number of M1-like macrophages soon after traumatic muscle injury is important for the recovery of skeletal muscle with less fibrosis, and this can be achieved by the transient expression of Granulocyte macrophage-colony stimulating factor (GM-CSF)[8].

Scaffolds[edit | edit source]

Biological scaffolds composed of extracellular matrix (ECM) proteins are commonly used in regenerative medicine and in surgical procedures for tissue reconstruction and regeneration. The scaffolds can promote the repair of volumetric muscle loss by providing a structural and biochemical framework. For smaller amounts of muscle loss, several tissue-derived scaffolds have been tested in animal models and translated into the clinic for surgical application.[2]

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  • Myogenic precursor cell survival and migration is greatly increased by using appropriate scaffold composition and growth factor delivery.
  • Controlling the microenvironment of injected myogenic cells using biological scaffolds enhance muscle regeneration.
  • Ideally, using an appropriate extracellular matrix (ECM) composition and stiffness, scaffolds should best replicate the the living and mechanical microenvironment.[3]

Fat Cell Transformation[edit | edit source]

Scientists have developed  a stem cell technique capable of regenerating any human tissue damaged by injury, disease or ageing The technique reprograms bone and fat cells into induced multipotent stem cells (iMS) and has successfully repaired bones and muscles in mice. The transplanted cells appear to follow instructions from adjacent cells and divide and mature in an orderly fashion. This efficient virus-free method of generating tissue regenerative stem cells brings us a step closer to realising stem cell therapy for repairing tissue injury in the human body.[9]

Anti-fibrotic therapy[edit | edit source]

Transforming growth factor beta 1 or TGF-β1 (see below) is expressed at high levels and plays an important role in the fibrotic cascade that occurs after the onset of muscle in that inactivate TGF-β1 signaling pathways reduces muscle fibrosis and, consequently, improve muscle healing, leading to a near complete recovery of lacerated muscle.

  • TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene

Mechanical Stimulation[edit | edit source]

Mechanical stimulation may offer a simple and effective approach to enhance skeletal muscle regeneration.

  • The direct stimulation of muscle tissue increases the transport of oxygen, nutrients, fluids, and waste removal from the site of the injury, which are all vital components of muscle health and repair. Studies looking at the principle of using mechanical stimulation to enhance regeneration or reduce formation of scarring or fibrosis could be applied to skeletal muscle regeneration are taking place.[1]

References[edit | edit source]

  1. 1.0 1.1 Harvard news Available from: https://news.harvard.edu/gazette/story/2016/01/mechanical-stimulation-shown-to-repair-muscle/ (accessed 12.4.2021)
  2. 2.0 2.1 2.2 Liu J, Saul D, Böker KO, Ernst J, Lehman W, Schilling AF. Current methods for skeletal muscle tissue repair and regeneration. BioMed research international. 2018 Apr 16;2018.Available from:https://www.hindawi.com/journals/bmri/2018/1984879/ (accessed 12.4.2021)
  3. 3.0 3.1 3.2 3.3 3.4 Laumonier T, Menetrey J. Muscle injuries and strategies for improving their repair. Journal of experimental orthopaedics. 2016 Dec;3(1):1-9.Available from:https://jeo-esska.springeropen.com/articles/10.1186/s40634-016-0051-7#Sec15 (accessed 11.4.2021)
  4. Engert JC, Berglund EB, Rosenthal N. Proliferation precedes differentiation in IGF-I-stimulated myogenesis. The Journal of cell biology. 1996 Oct 15;135(2):431-40.Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2121039/ (accessed 1.4.2021)
  5. National MS society Stem cells in MS Available from:https://www.nationalmssociety.org/Research/Research-News-Progress/Stem-Cells-in-MS (accessed 2.4.2021)
  6. Lo JH, Pong UK, Yiu T, Ong MT, Lee WY. Sarcopenia: Current treatments and new regenerative therapeutic approaches. Journal of orthopaedic translation. 2020 Apr 30.Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256062/ (last accessed 12.4.2021)
  7. Pan HC, Chin CS, Yang DY, Ho SP, Chen CJ, Hwang SM, Chang MH, Cheng FC. Human amniotic fluid mesenchymal stem cells in combination with hyperbaric oxygen augment peripheral nerve regeneration. Neurochemical research. 2009 Jul;34(7):1304-16.Available:https://pubmed.ncbi.nlm.nih.gov/19152028/ (accessed 12.4.2021)
  8. Martins L, Gallo CC, Honda TS, Alves PT, Stilhano RS, Rosa DS, Koh TJ, Han SW. Skeletal muscle healing by M1-like macrophages produced by transient expression of exogenous GM-CSF. Stem cell research & therapy. 2020 Dec;11(1):1-2.Available from:https://stemcellres.biomedcentral.com/articles/10.1186/s13287-020-01992-1#Sec19( accessed 11.4.2021)
  9. The Conversation Regenerating body parts: how we can transform fat cells into stem cells to repair spinal disc injuries Available from:https://theconversation.com/regenerating-body-parts-how-we-can-transform-fat-cells-into-stem-cells-to-repair-spinal-disc-injuries-57116 (accessed 11.4.2021)