Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2010 Jan 1.
Published in final edited form as: Clin Sports Med. 2009 Jan;28(1):1–11. doi: 10.1016/j.csm.2008.08.009

Stem Cells for the Treatment of Skeletal Muscle Injury

Andres J Quintero 1,2, Vonda J Wright 1,2, Freddie H Fu 1,2, Johhny Huard 1,2,*
PMCID: PMC2630112  NIHMSID: NIHMS84927  PMID: 19064161

Abstract

Skeletal muscle injuries are extremely common, accounting for up to 35-55% of all sports injuries and quite possibly impacting all musculoskeletal traumas. These injuries result in the formation of fibrosis that may lead to development of painful contractures, increases their risk for repeat injuries, and limits their ability to return to a baseline or pre-injury level of function. The development of successful therapies for these injuries must consider the pathophysiology of these musculoskeletal conditions. We discuss the direct use of muscle-derived stem cells and some key cell population dynamics, as well as the use of clinically applicable modalities which may enhance the local supply of stem cells to the zone of injury by promoting angiogenesis.

Keywords or phrases: Sports injury, stem cells, tissue engineering, fibrosis, regeneration, skeletal muscle

Introduction

Skeletal muscle injury can result form a variety of mechanisms, including contusion, strain, laceration, or a combination of these mechanisms.1-5 It is also possible for skeletal muscle injury to result from indirect sequelae of over-exertion or direct injury, such as via ischemia and neurologic impairment secondary to exercise-induced or traumatic compartment syndromes.6-15 These injuries are extremely common, accounting for up to 35-55% of all sports injuries and quite possibly impacting all musculoskeletal traumas.16-18 The associated morbidity is considerable, as these injuries portend professional and recreational athletes to develop painful contractures and muscle atrophy, require prolonged recovery periods, increase the risk for recurrent injury, and in some cases limit patients’ abilities to return to baseline or pre-injury levels of activity.1, 6, 19 Accordingly, significant efforts are being made to improve the current treatment of skeletal muscle trauma.

Currently, the treatment of these injuries by and large consists of rest, ice, compression, and elevation (RICE), although other advocated treatments include the local application of heat, immobilization, and passive range of motion exercises, as well as non-steroidal anti-inflammatory drugs (NSAIDs), intramuscular corticosteroids, and, in some cases, surgery.1-4 In many instances, however, these therapies remain sub-optimal. During the past decade, there have been sophisticated advances in rehabilitation, biomechanics, cell therapies, and tissue engineering with the goal of enhancing current therapies. As research in cell therapy and tissue engineering has progressed, it is clear that successful therapies must be based on an understanding of the basic pathophysiology of skeletal muscle injury.

Pathophysiology of Skeletal Muscle Injury

The pathophysiology of skeletal muscle injury is characterized by a sequence of events consisting of degeneration, inflammation, myofiber regeneration, and the formation of fibrotic scar tissue, as described below in detail and illustrated in Figure 1.

Figure 1. Skeletal muscle injury pathology.

Figure 1

After injury, there is a degeneration phase followed by inflammation. This inflammatory response locally recruits progenitor cells to the zone of injury for muscle repair. The reparative phase can last up to 3 weeks, and is followed by a deleterious rise of TGF-B that induces fibrosis, which places patients at increased risk for recurrent injury, developing painful contractures, and requiring lengthy recovery periods from which there is often an incomplete return to baseline function.

Degeneration and Inflammation

Immediately following injury, there is a phase of myofiber degeneration that is initiated by the release of proteases into the tissue stroma; these proteases autodigest myofibers and thereby release tissue debris along the zone of injury.20 Within the time frame that this occurs, there is a chemotaxis of neutrophils and macrophages to this area at which point the local debris is phagocytosed and processed by macrophages to induce a local inflammatory response.21-24 Although it appears that macrophages may in part be a culprit by initiating an inflammatory response, some studies indicate that these cells also secrete various growth factors that directly contribute to tissue regeneration. Additionally, macrophages stimulate the paracrine release of cytokines and other chemotactic factors by T-cells that may locally recruit progenitor and satellite cells with the capacity for muscle regeneration.25-31 Some of the critical cytokines that orchestrate this local response include interleukin [IL]-1, -6, and -8, as well as insulin growth factor [IGF]-1.

It is clear from this initial sequence of events, then, that the inflammatory response may be conducive to the repair of skeletal muscle after injury. In the event that this event is blunted, such as through the use of NSAIDs or intramuscular corticosteroid injections, the tangible clinical benefits of also blunting the classic inflammatory symptoms of pain (dolor), heat (calor), erythema (rubor), and swelling (tumor) must be weighed against the cost of potentially delaying and reducing the extent of tissue healing that may be mediated by infiltrating progenitor cells. Some evidence from animal studies suggests that the blocking the cyclooxygenase-2 pathway with prostaglandin inhibitors such as NSAIDs does indeed compromise the histological quality of muscle repair and may even result in a functional compromise. 32, 33 This may result in large part from the upregulation of transforming growth factor [TGF]-ß1, which inhibits myogenic precursor cells and augments fibrosis.34

Regeneration

While the degeneration phase is transient, the subsequent phase of myofiber regeneration is the first step in the schematic for skeletal muscle injury that has a long-term effect. This phase may begin as early as 24 hrs following injury, as evidenced by the cytokine-mediated induction of local satellite cells that previously lie dormant between the basal lamina and sarcolemma; it is not until at least 3-5 days after injury, however, that the complete formation of new, centronucleated myofibers can be detected histologically. 7, 27, 35

It is likely that a crucial event in the regeneration phase is the differentiation of satellite cells into myotubules and myofibers. To date, these progenitor cells are perhaps the best characterized, and are often referred to as “muscle stem cells” given their predilection to the myogenic lineage. There are, however, other populations isolated from skeletal muscle, including muscle side-population cells, mesoangioblasts, pericytes, and post-natal muscle-derived stem cells (MDSCs) that appear to be multipotent 36-42

While the origin and relationship of these additional progenitor cells to muscle stem cells remains to be fully elucidated, emerging evidence suggests that MDSCs represent a highly purified and unique population of stem cells that have several advantages for regenerative medicine over other populations. These advantages by and large consists of their longer-term survival after implantation into skeletal muscle as compared to myoblasts; their remarkable multi-potency (Figure 2), and their potential for long term regeneration, with up to 300 population doublings (PDs) prior to becoming senescent as compared to PDs of 130-250 for embryonic stem cells.37, 40, 43-46 Additionally, MDSCs can be efficiently transduced with antifibrotic and regenerative factors that may enhance skeletal muscle healing. 44, 47, 48

Figure 2. Multipotency of Muscle-Derived Stem Cells.

Figure 2

Our laboratory has previously isolated muscle derived stem cells from mice. These cells are remarkably pluripotent, and can undergo long term expansion. Accordingly, MDSCs are ideal for regenerative medicine.

Since the discovery of MDSCs, a topic of interest has been their origin. Recently, there is convincing evidence that these cells are likely derived from the vascular endothelium. 49, 50 Accordingly, a growing focus in research on skeletal muscle repair has not only involved finding ways to use MDSCs for repairing the zone of injury, but also to augment the local vascular supply to this site as a way to provide a steady source of these cells. 42, 44, 50-52

Fibrosis

Perhaps the greatest limitation for patients that results from the pathophysiology of skeletal muscle injury is the formation of dense fibrotic scar tissue. It is clear that fibrosis is induced by a deleterious rise in the cytokine Transforming Growth Factor (TGF)-B1 after injury.46 In the presence of this cytokine, MDSCs and other myogenic cells differentiate into myofibroblasts that produce collagen type I, the major component of fibrotic tissue.8, 34, 45, 53 Ultimately, fibrosis can prevent patients from returning to their baseline function, in part by preventing the formation of new axons toward myofibers, and contributes to a decline in muscle contractility and range of motion.54, 55 The pain that results from fibrosis also is a limiting factor in the recovery of patients, both during rehabilitation and in the long-term.

While not currently used clinically in this capacity or at all, several agents that block TGF-B1 have proven to be remarkably antifibrotic, including gamma-interferon, suramin and decorin.56-58 Fortunately, the commercially-available diuretic, losartan, has also been shown to have a significant antifibrotic effect along the zone of skeletal muscle injury in Sprague Dewy rats. 59 While clinical trials with this medication are feasible, their use must be cautioned in settings of musculoskeletal traumas and athletic injuries, where patients may oftentimes be dehydrated and thereby be at increased risk for developing acute renal insufficiency.

Skeletal Muscle Engineering with Muscle Derived Stem Cells

The transplantation of stem cells into aberrant or injured tissue has long been a central goal of regenerative medicine and tissue engineering. The translation of basic science research on muscle repair with autologous MDSCs to the bedside has been spearheaded by preliminary trials to treat stress urinary incontinence. One trial has resulted in successful cases over a one-year period following the implantation of these cells to restore detrusor muscle function, with 5 out of 8 females reporting improvements, one achieving complete continence, and none sustaining any adverse outcomes.60 Larger clinical trials using MDSCs to treat this disease entity are planned for the near future.

Presently, the majority of reports on research using stem cell therapies for muscle regeneration are limited to animal models. Successful results have been reported for Duchene Muscular Dystrophy models, in which dystrophin can be restored following the systemic delivery of various stem cells.40, 61, 62 Perhaps more relevant to sports injuries, Kinnaird et al developed an ischemic model in which Balb/C mice underwent ligation of the femoral artery; compared to controls, mice that later received distal injections of marrow-derived stromal cells on the affected limb displayed significantly better perfusion and appearance, had a lower incidence of autoamputation, and developed less fibrosis and atrophy.63

Although perhaps a more severe form of ischemia, this ischemic model may translate in part to the ischemia that may occur from an exercise-induced compartment syndrome, raising the possibility that the local injection of autologous stem cells early during the development of limb ischemia from such a mechanism is worthy of further investigation. Presently, although our laboratory is investigating the role of directly implanted MDSCs into contused skeletal muscle following contusion, we are unable to determine as of yet what the benefits to doing so may be. We hope that reports on this will follow in the near future.

Although the literature may often refer to MDSCs as a homogeneous population, these stem cells are quite heterogeneous, differing in how efficiently different populations regenerate skeletal muscle in vivo. Research on sex-related differences in the regeneration of skeletal muscle for Duchenne muscular dystrophy models shows that, regardless of the host’s sex, female MDCSs are significantly superior to male MDSCs to regenerate and repair skeletal muscle.52 The use of MDSCs to repair bone and cartilage is also influenced by the gender of the cells and the host animals, with the male MDSCs displaying a superior regeneration index than their female counterpart 64, 65 This may in large part be due to different embryonic developmental patterns that occur in female and male embryogenesis. Deasy et al also found that in skeletal muscle experiments where donor MDSCs are sex-matched, female hosts are also superior, a finding that is supported by other studies suggesting that the hormonal milieu of the female host skeletal muscle is better-suited for donor cell transplantation.66, 67 The role of immune rejection does not appear to explain the lower regeneration index of male donor cells transplanted into female hosts, as these sex differences were also identified when using severe combined immunodeficient host mice. This confirms that these sex differences may indeed occur because females are superior donors and hosts for MDSC-mediated skeletal muscle regeneration. While further studies are necessary to show a similar phenomenon with human cells, future therapeutic advances on skeletal muscle healing with MDSCs can greatly benefit from these important gender differences observed with MDSC.

Skeletal Muscle Engineering with Angiogenic Modalities: Exercise and Neuromuscular Electrical Stimulation

Aside from directly implanting stem cells into skeletal muscle, significant attention now focuses on promoting angiogenesis to activate resident satellite cells and provide a long-lasting portal through which MDSCs can derive, ultimately to aid in skeletal muscle healing. With clear evidence that exercise promotes cardiac and skeletal muscle perfusion, several studies now show this is because muscle contraction, such as through voluntary exercise or neuromuscular electrical stimulation, induces the formation of new vessels and the expansion of existing vascular trees. 68-70

Aside from promoting angiogenesis, several other mechanisms exist through which exercise can enhance healing. For instance, exercise increases the serum concentrations of matrix metalloproteinases (MMPs), which directly digest fibrotic scar tissue, regulate the secretion of pro-regenerative growth factors such as insulin-like growth factor, and may also mobilize stem cells. 71, 72, 73, 74 Moreover, several studies show that exercise-induced hypoxia promoted skeletal muscle healing by elevating the circulating concentrations of hypoxia-induced factor, stromal-cell derived factor, and erythropoietin, each of which mobilizes endothelial progenitor stem cells from the bone marrow to coordinate the neovascularization of hypoxic tissues. 75-82 In light of this information, there is certainly the potential for combining MMPs and stem cells for direct implantation, as well as MMPs with conservative means of promoting angiogenesis, such as voluntary exercise and, as will be discussed below, neuromuscular electrical stimulation.

Based on this information, it is possible that, at least for some instances of skeletal muscle injury, the more traditional therapy of rest may jeopardize an opportunity to locally recruit stem cells to the zone of injury. It is also possible that through controlled and monitored exercise regimens in appropriately selected patients, perhaps initiated prior to the completion or the regeneration phase of skeletal muscle injury, the activation and infiltration of stem cells to the zone of injury may increase and enhance regeneration. Further studies may be necessary to determine whether rest is deleterious to healing after injury, whether certain exercises are safe and clinically beneficial, and, if so, whether the timing of exercise rehabilitation relative to the onset of injury influences outcomes.

As with exercise, another modality that appears to promote angiogenesis and skeletal muscle healing after injury is neuromuscular electrical stimulation (NMES). While the data linking stem cell activation and recruitment to NMES is lacking, there is evidence that this modality promotes angiogenesis. 70, 83 As with exercise, it appears that tissue hypoxia induced during NMES may play a role in promoting angiogenesis, although the exact mechanism requires further elucidation. 84 Our laboratory has demonstrated that amongst 9-week old male C57BL/10J mice, prophylactic and post-injury NMES significantly enhances the percent capillary area of the tibialis anterior (unpublished data.) Additionally, at 5 and 10 days after injury, the percentage regeneration significantly increases and the percentage fibrosis significantly decreases along the zone of injury in mice undergoing prophylactic electrical stimulation 3 times weekly for 2 weeks (unpublished data.) Among mice undergoing post-injury NMES, we had the same findings for fibrosis, but were only able to detect a significant increase in the percentage regeneration at 10 days after injury (unpublished data).

One reason for why prophylactic NMES may be superior to post-injury stimulation is that by promoting angiogenesis early on, the regenerative phase of skeletal muscle injury will begin to occur in the presence of more MDSCs derived from the vascular endothelium, as well as more infiltrating growth factors that activate dormant satellite cells. With post-injury stimulation, these cells and factors may come into the zone of injury beyond the optimal time window for tissue repair. While speculative on our part at the present time, this would be consistent with our proposition above that early exercise rehabilitation programs may be beneficial in some cases of skeletal muscle injury, although clinical studies are necessary to support this. This may also be similar to the process of fracture repair, in which relatively early fracture stabilization is oftentimes necessary to prevent the progression to fracture non-union.85 Accordingly, more studies are required to better delineate the temporal relationship of skeletal muscle injury, NMES, and other therapeutic interventions such as the implantation of stem cells directly into the zone of injury to optimize skeletal muscle healing responses.

Summary

Amongst the most commonly prescribed treatments for skeletal muscle injuries are rest, ice application, compression, and elevation (RICE), as well as heat application and either immobilization or passive range of motion exercises. In many instances, however, these therapies remain sub-optimal.

Based on our current knowledge, the inflammatory response that follows injury promotes skeletal muscle regeneration, perhaps in part by locally recruiting stem cells via chemotaxis to the zone of injury. While the therapeutic administration of steroids and NSAIDs may prove symptomatic relief by combating inflammation, there is evidence that this blunts the regenerative response and may actually promote fibrosis.

Current research has linked angiogenesis to skeletal muscle healing, and indicates that blood vessels are likely the origin of MDSCs. As voluntary exercise and neuromuscular electrical stimulation both promote angiogenesis, it is possible that in appropriately selected patients, a feasible therapeutic alternative to rest and immobilization for skeletal muscle injury may consists of controlled and monitored exercise programs as well as NMES; future studies may need to determine if rest is deleterious to skeletal muscle healing, as well as which exercises are safe and clinically efficacious for various patterns and locations of injury. Similarly, a feasible alternative to current pharmacologic therapies may include losartan, although the use of this medication for treating skeletal muscle injury is not currently approved by the United States Food and Drug Administration.

In light of recent successful clinical trials on the direct implantation of MDSCs to treat urinary incontinence secondary to detrusor muscle dysfunction, the future of stem cell therapy for skeletal muscle injury may be closer than ever to translation into clinical studies. Such studies must continue to characterize and make use of the optimal MDSC populations, as well as examine MDSC transplantation in combination with pro-regenerative and antifibrotic agents such as MMPs and losartan.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Lehto MU, Jarvinen MJ. Muscle injuries, their healing process and treatment. Ann Chir Gynaecol. 1991;80(2):102–108. [PubMed] [Google Scholar]
  • 2.Levine WN, Bergfeld JA, Tessendorf W, Moorman CT., 3rd Intramuscular corticosteroid injection for hamstring injuries. A 13-year experience in the National Football League. Am J Sports Med. 2000 May-Jun;28(3):297–300. doi: 10.1177/03635465000280030301. [DOI] [PubMed] [Google Scholar]
  • 3.Jarvinen MJ, Lehto MU. The effects of early mobilisation and immobilisation on the healing process following muscle injuries. Sports Med. 1993 Feb;15(2):78–89. doi: 10.2165/00007256-199315020-00002. [DOI] [PubMed] [Google Scholar]
  • 4.Hurme T, Kalimo H, Lehto M, Jarvinen M. Healing of skeletal muscle injury: an ultrastructural and immunohistochemical study. Med Sci Sports Exerc. 1991 Jul;23(7):801–810. [PubMed] [Google Scholar]
  • 5.Jarvinen TA, Jarvinen TL, Kaariainen M, Kalimo H, Jarvinen M. Muscle injuries: biology and treatment. Am J Sports Med. 2005 May;33(5):745–764. doi: 10.1177/0363546505274714. [DOI] [PubMed] [Google Scholar]
  • 6.Huard J, Li Y, Fu FH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am. 2002 May;84-A(5):822–832. [PubMed] [Google Scholar]
  • 7.Li Y, C J, Huard J. Muscle Injury and Repair. Curr Opin Orthop. 2001;12:409–415. [Google Scholar]
  • 8.Cetinus E, Uzel M, Bilgic E, Karaoguz A, Herdem M. Exercise induced compartment syndrome in a professional footballer. Br J Sports Med. 2004 Apr;38(2):227–229. doi: 10.1136/bjsm.2003.004630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Edmundsson D, Toolanen G, Sojka P. Chronic compartment syndrome also affects nonathletic subjects: a prospective study of 63 cases with exercise-induced lower leg pain. Acta Orthop. 2007 Feb;78(1):136–142. doi: 10.1080/17453670610013547. [DOI] [PubMed] [Google Scholar]
  • 10.Howard JL, Mohtadi NG, Wiley JP. Evaluation of outcomes in patients following surgical treatment of chronic exertional compartment syndrome in the leg. Clin J Sport Med. 2000 Jul;10(3):176–184. doi: 10.1097/00042752-200007000-00005. [DOI] [PubMed] [Google Scholar]
  • 11.Leppilahti J, Tervonen O, Herva R, Karinen J, Puranen J. Acute bilateral exercise-induced medial compartment syndrome of the thigh. Correlation of repeated MRI with clinicopathological findings. Int J Sports Med. 2002 Nov;23(8):610–615. doi: 10.1055/s-2002-35529. [DOI] [PubMed] [Google Scholar]
  • 12.Levine WN. Exercise-induced compartment syndrome. Am J Knee Surg. 1995 Fall;8(4):119. [PubMed] [Google Scholar]
  • 13.Litwiller DV, Amrami KK, Dahm DL, et al. Chronic exertional compartment syndrome of the lower extremities: improved screening using a novel dual birdcage coil and in-scanner exercise protocol. Skeletal Radiol. 2007 Nov;36(11):1067–1075. doi: 10.1007/s00256-007-0360-0. [DOI] [PubMed] [Google Scholar]
  • 14.Robinson MS, Parekh AA, Smith WR, Shannon MJ, Morgan SJ. Bilateral Exercise Induced Exertional Compartment Syndrome Resulting In Acute Compartment Loss: A Case Report. J Trauma. 2007 Mar 14; doi: 10.1097/01.ta.0000234668.25044.cf. [DOI] [PubMed] [Google Scholar]
  • 15.Schissel DJ, Godwin J. Effort-related chronic compartment syndrome of the lower extremity. Mil Med. 1999 Nov;164(11):830–832. [PubMed] [Google Scholar]
  • 16.Dyson R, Buchanan M, Hale T. Incidence of sports injuries in elite competitive and recreational windsurfers. Br J Sports Med. 2006 Apr;40(4):346–350. doi: 10.1136/bjsm.2005.023077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Stevenson MR, Hamer P, Finch CF, Elliot B, Kresnow M. Sport, age, and sex specific incidence of sports injuries in Western Australia. Br J Sports Med. 2000 Jun;34(3):188–194. doi: 10.1136/bjsm.34.3.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Brooks JH, Fuller CW, Kemp SP, Reddin DB. Incidence, risk, and prevention of hamstring muscle injuries in professional rugby union. Am J Sports Med. 2006 Aug;34(8):1297–1306. doi: 10.1177/0363546505286022. [DOI] [PubMed] [Google Scholar]
  • 19.Garrett WE., Jr Muscle strain injuries: clinical and basic aspects. Med Sci Sports Exerc. 1990 Aug;22(4):436–443. [PubMed] [Google Scholar]
  • 20.Mbebi C, Hantai D, Jandrot-Perrus M, Doyennette MA, Verdiere-Sahuque M. Protease nexin I expression is up-regulated in human skeletal muscle by injury-related factors. J Cell Physiol. 1999 Jun;179(3):305–314. doi: 10.1002/(SICI)1097-4652(199906)179:3<305::AID-JCP8>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  • 21.Orimo S, Hiyamuta E, Arahata K, Sugita H. Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle Nerve. 1991 Jun;14(6):515–520. doi: 10.1002/mus.880140605. [DOI] [PubMed] [Google Scholar]
  • 22.Tidball JG, Berchenko E, Frenette J. Macrophage invasion does not contribute to muscle membrane injury during inflammation. J Leukoc Biol. 1999 Apr;65(4):492–498. [PubMed] [Google Scholar]
  • 23.Warren GL, Hulderman T, Jensen N, et al. Physiological role of tumor necrosis factor alpha in traumatic muscle injury. Faseb J. 2002 Oct;16(12):1630–1632. doi: 10.1096/fj.02-0187fje. [DOI] [PubMed] [Google Scholar]
  • 24.Mitchell CA, McGeachie JK, Grounds MD. Cellular differences in the regeneration of murine skeletal muscle: a quantitative histological study in SJL/J and BALB/c mice. Cell Tissue Res. 1992 Jul;269(1):159–166. doi: 10.1007/BF00384736. [DOI] [PubMed] [Google Scholar]
  • 25.Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol. 2005 Feb;288(2):R345–353. doi: 10.1152/ajpregu.00454.2004. [DOI] [PubMed] [Google Scholar]
  • 26.Cantini M, Carraro U. Macrophage-released factor stimulates selectively myogenic cells in primary muscle culture. J Neuropathol Exp Neurol. 1995 Jan;54(1):121–128. doi: 10.1097/00005072-199501000-00014. [DOI] [PubMed] [Google Scholar]
  • 27.Hurme T, Kalimo H. Activation of myogenic precursor cells after muscle injury. Med Sci Sports Exerc. 1992 Feb;24(2):197–205. [PubMed] [Google Scholar]
  • 28.Massimino ML, Rapizzi E, Cantini M, et al. ED2+ macrophages increase selectively myoblast proliferation in muscle cultures. Biochem Biophys Res Commun. 1997 Jun 27;235(3):754–759. doi: 10.1006/bbrc.1997.6823. [DOI] [PubMed] [Google Scholar]
  • 29.Robertson TA, Maley MA, Grounds MD, Papadimitriou JM. The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res. 1993 Aug;207(2):321–331. doi: 10.1006/excr.1993.1199. [DOI] [PubMed] [Google Scholar]
  • 30.DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock. 1995 Oct;4(4):233–240. [PubMed] [Google Scholar]
  • 31.Summan M, Warren GL, Mercer RR, et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am J Physiol Regul Integr Comp Physiol. 2006 Jun;290(6):R1488–1495. doi: 10.1152/ajpregu.00465.2005. [DOI] [PubMed] [Google Scholar]
  • 32.Shen W, Prisk V, Li Y, Foster W, Huard J. Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: the role of PGE2 and PGF2alpha. J Appl Physiol. 2006 Oct;101(4):1215–1221. doi: 10.1152/japplphysiol.01331.2005. [DOI] [PubMed] [Google Scholar]
  • 33.Mishra DK, Friden J, Schmitz MC, Lieber RL. Anti-inflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function. J Bone Joint Surg Am. 1995 Oct;77(10):1510–1519. doi: 10.2106/00004623-199510000-00005. [DOI] [PubMed] [Google Scholar]
  • 34.Shen W, Li Y, Tang Y, Cummins J, Huard J. NS-398, a cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis. Am J Pathol. 2005 Oct;167(4):1105–1117. doi: 10.1016/S0002-9440(10)61199-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Rantanen J, Hurme T, Lukka R, Heino J, Kalimo H. Satellite cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for two different populations of satellite cells. Lab Invest. 1995 Mar;72(3):341–347. [PubMed] [Google Scholar]
  • 36.Peault B, Rudnicki M, Torrente Y, et al. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol Ther. 2007 May;15(5):867–877. doi: 10.1038/mt.sj.6300145. [DOI] [PubMed] [Google Scholar]
  • 37.Lee JY, Qu-Petersen Z, Cao B, et al. Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol. 2000 Sep 4;150(5):1085–1100. doi: 10.1083/jcb.150.5.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Asakura A, Komaki M, Rudnicki M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation. 2001 Oct;68(45):245–253. doi: 10.1046/j.1432-0436.2001.680412.x. [DOI] [PubMed] [Google Scholar]
  • 39.Wada MR, Inagawa-Ogashiwa M, Shimizu S, Yasumoto S, Hashimoto N. Generation of different fates from multipotent muscle stem cells. Development. 2002 Jun;129(12):2987–2995. doi: 10.1242/dev.129.12.2987. [DOI] [PubMed] [Google Scholar]
  • 40.Cao B, Zheng B, Jankowski RJ, et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol. 2003 Jul;5(7):640–646. doi: 10.1038/ncb1008. [DOI] [PubMed] [Google Scholar]
  • 41.Musgrave DS, Fu FH, Huard J. Gene therapy and tissue engineering in orthopaedic surgery. J Am Acad Orthop Surg. 2002 Jan-Feb;10(1):6–15. doi: 10.5435/00124635-200201000-00003. [DOI] [PubMed] [Google Scholar]
  • 42.Peng H, Huard J. Muscle-derived stem cells for musculoskeletal tissue regeneration and repair. Transpl Immunol. 2004 Apr;12(34):311–319. doi: 10.1016/j.trim.2003.12.009. [DOI] [PubMed] [Google Scholar]
  • 43.Deasy BM, Gharaibeh BM, Pollett JB, et al. Long-term self-renewal of postnatal muscle-derived stem cells. Mol Biol Cell. 2005 Jul;16(7):3323–3333. doi: 10.1091/mbc.E05-02-0169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Qu-Petersen Z, Deasy B, Jankowski R, et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol. 2002 May 27;157(5):851–864. doi: 10.1083/jcb.200108150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Li Y, Huard J. Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. Am J Pathol. 2002 Sep;161(3):895–907. doi: 10.1016/S0002-9440(10)64250-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Li Y, Foster W, Deasy BM, et al. Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol. 2004 Mar;164(3):1007–1019. doi: 10.1016/s0002-9440(10)63188-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Irintchev A, Wernig A. Muscle damage and repair in voluntarily running mice: strain and muscle differences. Cell Tissue Res. 1987 Sep;249(3):509–521. doi: 10.1007/BF00217322. [DOI] [PubMed] [Google Scholar]
  • 48.Qu Z, Balkir L, van Deutekom JC, Robbins PD, Pruchnic R, Huard J. Development of approaches to improve cell survival in myoblast transfer therapy. J Cell Biol. 1998 Sep 7;142(5):1257–1267. doi: 10.1083/jcb.142.5.1257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Tavian M, Zheng B, Oberlin E, et al. The vascular wall as a source of stem cells. Ann N Y Acad Sci. 2005 Jun;1044:41–50. doi: 10.1196/annals.1349.006. [DOI] [PubMed] [Google Scholar]
  • 50.Zheng B, Cao B, Crisan M, et al. Prospective identification of myogenic endothelial cells in human skeletal muscle. Nat Biotechnol. 2007 Sep;25(9):1025–1034. doi: 10.1038/nbt1334. [DOI] [PubMed] [Google Scholar]
  • 51.Deasy BM, Li Y, Huard J. Tissue engineering with muscle-derived stem cells. Curr Opin Biotechnol. 2004 Oct;15(5):419–423. doi: 10.1016/j.copbio.2004.08.004. [DOI] [PubMed] [Google Scholar]
  • 52.Deasy BM, Lu A, Tebbets JC, et al. A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J Cell Biol. 2007 Apr 9;177(1):73–86. doi: 10.1083/jcb.200612094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Ghosh AK. Factors involved in the regulation of type I collagen gene expression: implication in fibrosis. Exp Biol Med (Maywood) 2002 May;227(5):301–314. doi: 10.1177/153537020222700502. [DOI] [PubMed] [Google Scholar]
  • 54.Kaariainen M, Jarvinen T, Jarvinen M, Rantanen J, Kalimo H. Relation between myofibers and connective tissue during muscle injury repair. Scand J Med Sci Sports. 2000 Dec;10(6):332–337. doi: 10.1034/j.1600-0838.2000.010006332.x. [DOI] [PubMed] [Google Scholar]
  • 55.Shanmugasundaram TK. Post-injection fibrosis of skeletal muscle: a clinical problem. A personal series of 169 cases. Int Orthop. 1980;4(1):31–37. doi: 10.1007/BF00266601. [DOI] [PubMed] [Google Scholar]
  • 56.Foster W, Li Y, Usas A, Somogyi G, Huard J. Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res. 2003 Sep;21(5):798–804. doi: 10.1016/S0736-0266(03)00059-7. [DOI] [PubMed] [Google Scholar]
  • 57.Fukushima K, Badlani N, Usas A, Riano F, Fu F, Huard J. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med. 2001 Jul-Aug;29(4):394–402. doi: 10.1177/03635465010290040201. [DOI] [PubMed] [Google Scholar]
  • 58.Kloen P, Jennings CL, Gebhardt MC, Springfield DS, Mankin HJ. Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines. Eur J Cancer. 1994;30A(5):678–682. doi: 10.1016/0959-8049(94)90544-4. [DOI] [PubMed] [Google Scholar]
  • 59.Bedair HS, K T, Quintero AJ, et al. Angiotensin II Receptor Blockade Administered After Injury Improves Muscle Regeneration and Decreases Fibrosis in Normal Skeletal Muscle. American Journal of Sports Medicine. 2008 doi: 10.1177/0363546508315470. In press. [DOI] [PubMed] [Google Scholar]
  • 60.Carr LK, Steele D, Steele S, et al. 1-year follow-up of autologous muscle-derived stem cell injection pilot study to treat stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2008 Jan 19; doi: 10.1007/s00192-007-0553-z. [DOI] [PubMed] [Google Scholar]
  • 61.Torrente Y, Tremblay JP, Pisati F, et al. Intraarterial injection of muscle-derived CD34(+)Sca-1(+) stem cells restores dystrophin in mdx mice. J Cell Biol. 2001 Jan 22;152(2):335–348. doi: 10.1083/jcb.152.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Bachrach E, Perez AL, Choi YH, et al. Muscle engraftment of myogenic progenitor cells following intraarterial transplantation. Muscle Nerve. 2006 Jul;34(1):44–52. doi: 10.1002/mus.20560. [DOI] [PubMed] [Google Scholar]
  • 63.Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004 Mar 30;109(12):1543–1549. doi: 10.1161/01.CIR.0000124062.31102.57. [DOI] [PubMed] [Google Scholar]
  • 64.Corsi KA, Pollett JB, Phillippi JA, Usas A, Li G, Huard J. Osteogenic potential of postnatal skeletal muscle-derived stem cells is influenced by donor sex. J Bone Miner Res. 2007 Oct;22(10):1592–1602. doi: 10.1359/jbmr.070702. [DOI] [PubMed] [Google Scholar]
  • 65.Matsumoto T, K S, Meszaros LB, Corsi KA, Cooper GM, Li G, Usas A, Osawa A, Fu FH, Huard J. Potential of Muscle-Derived Stem Cells: Implication for Cartilage Regeneration & Repair. Arthritis and Rheumatism. 2008 doi: 10.1002/art.24125. In press. [DOI] [PubMed] [Google Scholar]
  • 66.Steinlein P, Wessely O, Meyer S, Deiner EM, Hayman MJ, Beug H. Primary, self-renewing erythroid progenitors develop through activation of both tyrosine kinase and steroid hormone receptors. Curr Biol. 1995 Feb 1;5(2):191–204. doi: 10.1016/s0960-9822(95)00040-6. [DOI] [PubMed] [Google Scholar]
  • 67.Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992 Jul 3;257(5066):88–91. doi: 10.1126/science.1621100. [DOI] [PubMed] [Google Scholar]
  • 68.Bellafiore M, Sivverini G, Palumbo D, et al. Increased cx43 and angiogenesis in exercised mouse hearts. Int J Sports Med. 2007 Sep;28(9):749–755. doi: 10.1055/s-2007-964899. [DOI] [PubMed] [Google Scholar]
  • 69.Efthimiadou A, Asimakopoulos B, Nikolettos N, et al. The angiogenetic effect of intramuscular administration of b-FGF and a-FGF on cardiac muscle: the influence of exercise on muscle angiogenesis. J Sports Sci. 2006 Aug;24(8):849–854. doi: 10.1080/02640410500245629. [DOI] [PubMed] [Google Scholar]
  • 70.Ljubicic V, Adhihetty PJ, Hood DA. Application of animal models: chronic electrical stimulation-induced contractile activity. Can J Appl Physiol. 2005 Oct;30(5):625–643. doi: 10.1139/h05-144. [DOI] [PubMed] [Google Scholar]
  • 71.Suhr F, Brixius K, de Marees M, et al. Effects of short-term vibration and hypoxia during high-intensity cycling exercise on circulating levels of angiogenic regulators in humans. J Appl Physiol. 2007 Aug;103(2):474–483. doi: 10.1152/japplphysiol.01160.2006. [DOI] [PubMed] [Google Scholar]
  • 72.Bedair H, Liu TT, Kaar JL, et al. Matrix metalloproteinase-1 therapy improves muscle healing. J Appl Physiol. 2007 Jun;102(6):2338–2345. doi: 10.1152/japplphysiol.00670.2006. [DOI] [PubMed] [Google Scholar]
  • 73.Fowlkes JL, Serra DM, Nagase H, Thrailkill KM. MMPs are IGFBP-degrading proteinases: implications for cell proliferation and tissue growth. Ann N Y Acad Sci. 1999 Jun 30;878:696–699. doi: 10.1111/j.1749-6632.1999.tb07765.x. [DOI] [PubMed] [Google Scholar]
  • 74.Fowlkes JL, Serra DM, Bunn RC, Thrailkill KM, Enghild JJ, Nagase H. Regulation of insulin-like growth factor (IGF)-I action by matrix metalloproteinase-3 involves selective disruption of IGF-I/IGF-binding protein-3 complexes. Endocrinology. 2004 Feb;145(2):620–626. doi: 10.1210/en.2003-0636. [DOI] [PubMed] [Google Scholar]
  • 75.Tepper OM, Capla JM, Galiano RD, et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood. 2005 Feb 1;105(3):1068–1077. doi: 10.1182/blood-2004-03-1051. [DOI] [PubMed] [Google Scholar]
  • 76.Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002 May 31;109(5):625–637. doi: 10.1016/s0092-8674(02)00754-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004 Aug;10(8):858–864. doi: 10.1038/nm1075. [DOI] [PubMed] [Google Scholar]
  • 78.Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R977–988. doi: 10.1152/ajpregu.00577.2003. [DOI] [PubMed] [Google Scholar]
  • 79.Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996 Sep;16(9):4604–4613. doi: 10.1128/mcb.16.9.4604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Jelkmann W. Biology of erythropoietin. Clin Investig. 1994;72(6 Suppl):S3–10. [PubMed] [Google Scholar]
  • 81.Bahlmann FH, De Groot K, Spandau JM, et al. Erythropoietin regulates endothelial progenitor cells. Blood. 2004 Feb 1;103(3):921–926. doi: 10.1182/blood-2003-04-1284. [DOI] [PubMed] [Google Scholar]
  • 82.Bahlmann FH, DeGroot K, Duckert T, et al. Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int. 2003 Nov;64(5):1648–1652. doi: 10.1046/j.1523-1755.2003.00279.x. [DOI] [PubMed] [Google Scholar]
  • 83.Nagasaka M, Kohzuki M, Fujii T, et al. Effect of low-voltage electrical stimulation on angiogenic growth factors in ischaemic rat skeletal muscle. Clin Exp Pharmacol Physiol. 2006 Jul;33(7):623–627. doi: 10.1111/j.1440-1681.2006.04417.x. [DOI] [PubMed] [Google Scholar]
  • 84.Hudlicka O, Milkiewicz M, Cotter MA, Brown MD. Hypoxia and expression of VEGF-A protein in relation to capillary growth in electrically stimulated rat and rabbit skeletal muscles. Exp Physiol. 2002 May;87(3):373–381. doi: 10.1113/eph8702285. [DOI] [PubMed] [Google Scholar]
  • 85.Sumner-Smith G. Delayed unions and nonunions. Diagnosis, pathophysiology, and treatment. Vet Clin North Am Small Anim Pract. 1991 Jul;21(4):745–760. doi: 10.1016/s0195-5616(91)50082-6. [DOI] [PubMed] [Google Scholar]

RESOURCES