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The involvement of the TNF-alpha system in skeletal muscle in response to marked overuse
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.ORCID iD: 0000-0003-0795-8476
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Painful conditions having the origin within the musculoskeletal system is a common cause for people to seek medical care. Between 20-40% of all visits to the primal care in Sweden are coupled to pain from the musculoskeletal system. Muscle pain and impaired muscle function can be caused by muscles being repetitively overused and/or via heavy load. Skeletal muscle is a dynamic tissue which can undergo changes in order to fulfill what is best for optimal function. However, if the load is too heavy, morphological changes including necrosis, as well as pain can occur. The extension of the skeletal muscle is the tendon. Tendinopathy refers to illness and pain of the tendon. The peritendinous tissue is of importance in the features related to tendon pain. Common tendons/origins being afflicted by tendinopathy/pain are the Achilles tendon and the extensor origin at the elbow region.    Tumor necrosis factor alpha (TNF-alpha) is a cytokine that is involved in several biological processes. It is well-known for its involvement in the immune system and is an important target for inflammatory disorders such as rheumatoid arthritis. It is not known to what extent the TNF-alpha system is involved in the process of muscle inflammation and damage due to overuse.

   Studies were conducted on rabbit and human tissue, tissues that either had undergone an excessive loading activity or tissue that was removed with surgery due to painful conditions. The tissues were evaluated via staining for morphology, in situ hybridization and immunofluorescence.

   Unilateral experimental overuse of rabbit muscle (soleus muscle) led to morphological changes in the soleus muscle tissue bilaterally. The longer the experiment extended, the more was the tissue affected. This included infiltration of white blood cells in the tissue (myositis) and abnormal muscle fiber appearances. TNF-alpha mRNA was seen in white blood cells, in muscle fibers interpreted to be in a reparative stage and in white blood cells that had infiltrated into necrotic muscle fibers.  There was an upregulation in expressions of TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2) in muscles that were markedly overused, with expressions in white blood cells, fibroblasts, blood vessel walls and muscle fibers. Immunoreactions for the receptors were seen in nerve fascicles of markedly overused muscles but only occasionally in normal muscles. The upregulations were seen for both experimental and contralateral sides. Overall the two receptors showed somewhat different expression patterns. Tendinopathy is associated with an increase in blood flow and infiltration of white blood cells in the tissue adjacent to the tendon. It is called the peritendinous tissue and is also richly innervated. The white blood cells and the blood vessels walls in this tissue were showing immunoreaction for TNFR1 and TNFR2. Two types of nerve fascicles were found in this tissue, one normally appearing when staining for nerve markers and one type with signs of axonal loss. The latter had clearly strong immunoreactions for TNFR1 and TNFR2.

   The findings suggest that the TNF-alpha system is involved in both myopathies occurring due to overuse and in features in the peritendinous tissue in the tendinopathy situation. TNF-alpha and its receptors seem to be involved in degeneration but also in regeneration and healing of the tissue. The findings also suggest that TNF-alpha has effects on nerves showing axonal loss. The changes in the TNF-alpha system were seen both on the experimental side and contralaterally.

Abstract [sv]

Smärta och funktionsbortfall från rörelseapparaten är vanligt förekommande. Mellan 20-40% av alla besök i primärvården är kopplade till smärta från rörelseapparaten. Det är också en vanlig orsak till sjukfrånvaro. Överansträngning inklusive repetitivt enformigt muskelarbete kan leda till muskelsmärta och bristande muskelfunktion (ex nedsatt styrka och uthållighet, inskränkt rörlighet). Muskelvävnad är en dynamisk vävnad som kan ändras utefter vilka påfrestningar den utsätts för och därigenom vilka behov den ställs inför. Men om belastningen blir för hård, alternativt återhämtningen blir för kort, kan negativa förändringar i vävnadsstrukturen uppstå, inklusive celldöd och vävnadsskada.

Förlängningen av muskeln är senan. Senan är den vävnad som förbinder muskeln med skelettet. Tendinopati innefattar smärtsamma sjukdomstillstånd i senan. När sjukdom i en sena uppstår, exempelvis en smärtande hälsena, har man sett att den lösa bindväven som omger senan är av betydelse. Den genomgår morfologiska förändringar och man tror att det är den som är med och bidrar till smärtan vid tillståndet. Akillessenan och ”tennis-armbåge” är vanliga ställen för tendinopati. Akillessenan förbinder den trehövdade vadmuskeln med hälbenet. Tennis-armbåge omfattar ett område för flera musklers ursprung vid armbågen. Dessa muskler ansvarar framför allt för att sträcka i handleden.

TNF-alfa är en signalsubstans som är involverad i flertalet biologiska processer. Den är känd för sin del i immunförsvaret och den är ett viktigt mål för behandling av autoimmuna sjukdomar som exempelvis reumatoid artrit. Det är inte känt om TNF-alfa är inblandad i processen som uppstår vid muskelinflammation/muskelskada efter kraftig överansträngning. TNF-alfa har flera receptorer, i det här arbetet har utbredning av TNFR1 och TNFR2 analyserats.

Studier har utförts på djur (kaniner) och människa. Kaniner har genomgått ett träningsexperiment, där de utsatts för repetitiva muskelkontraktioner som lett till överansträngningsskador och muskelinflammation. Den muskel som studerats är soleus-muskeln, en del i den trehövdade vadmuskeln. Vävnadsprover har tagits från patienter med smärta i Akillessenan eller tennisarmbåge. Vävnadsproverna från kanin och människa har analyserats med färgningar för morfologi, immunohistokemi för detektering av TNF-alfa och dess receptorer samt för in situ hybridisering för detektion av mRNA i TNF-alfa systemet. Parallellt med färgningar för faktorerna i TNF-alfa systemet har uttryck för andra faktorer studerats. Ensidig överbelastning hos kaniner ledde till samma morfologiska förändringar på båda sidor, det vill säga även i muskeln i det ben som inte hade genomgått träningsexperimentet. Ju längre experimentet pågick, desto större blev de morfologiska förändringarna. TNF-alfa sågs i vita blodkroppar, TNF-alfa mRNA sågs även i förändrade muskelfibrer. Resultatet av parallella dubbelfärgningar tolkades som att dessa muskelfibrer antingen var i en regenererande process eller i en destruktiv process. TNFR1 och TNFR2 uttrycktes i större utsträckning ju längre experimentet pågick och ju mer muskelvävnaden var påverkad av inflammation. TNF receptorer sågs i vita blodkroppar, fibroblaster, muskelfibrer och nervstrukturer hos experimentdjuren. Det såg lika ut på båda sidor, inklusive det ben som inte ingått i experimentet. De två receptorerna skilde sig åt i uttryck.

Vävnad från patienter med smärtande senor/smärta vid muskelursprungs-region genomgick också färgningar för faktorer i TNF-alfa systemet. Man kunde se att den lösa bindväven runt senan (den peritendinösa vävnaden) innehöll mycket blodkärl och nerver. De nerver som sågs i denna vävnad var av två typer, en som såg normal ut och en typ som uppvisade tecken på förlust av axoner. Den senare varianten hade en tydlig uppreglering av båda TNF receptorerna.

Dessa resultat tyder på att TNF-alfa systemet är involverat i muskelsjukdomar som rör muskelinflammation till följd av kraftig överansträngning och i processerna i bindväven vid smärtande senor. TNF-alfa och dess receptorer verkar vara inblandade i både nedbrytning och uppbyggnad av muskelvävnad, samt påverka nerver som visar tecken på förlust av axoner. Förändringarna i TNF-alfa systemet sågs både på experimentsidan och kontralateralt.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2017. , p. 65
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1932
Keywords [en]
TNF-alpha, TNFR1, TNFR2, muscle damage, myositis, peritendinous tissue, tendinopathy
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:umu:diva-141942ISBN: 978-91-7601-802-6 (print)OAI: oai:DiVA.org:umu-141942DiVA, id: diva2:1157408
Public defence
2017-12-08, N320, Umeå Universitet, Naturvetarhuset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2017-11-17 Created: 2017-11-15 Last updated: 2018-06-09Bibliographically approved
List of papers
1. TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.
Open this publication in new window or tab >>TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.
2012 (English)In: International Journal of Rheumatology, ISSN 1687-9260, E-ISSN 1687-9279, Vol. 2012, p. 637452-Article in journal (Refereed) Published
Abstract [en]

The importance of TNF-alpha in arthritis is well documented. It may be that TNF-alpha is also markedly involved in muscle inflammation (myositis). An animal model where this can be investigated is needed. A newly developed rabbit myositis model involving pronounced muscle overuse and local injections of substances having proinflammatory effects was therefore used in the present study. The aim was to investigate the patterns of TNF-alpha expression in the developing myositis and to evaluate the usefulness of this myositis model for further TNF-alpha research. Human rheumatoid arthritis (RA) synovial tissue was examined as a reference. TNF-alpha immunoexpression and TNF-alpha mRNA, visualized via in situ hybridization, were detected in cells in the inflammatory infiltrates of the affected muscle (soleus muscle). Coexistence of TNF-alpha and CD68 immunoreactions was noted, suggesting that the TNF-alpha reactive cells are macrophages. Expression of TNF-alpha mRNA was also noted in muscle fibers and blood vessel walls in areas with inflammation. These findings demonstrate that TNF-alpha is highly involved in the myositis process. The model can be used in further studies evaluating the importance of TNF-alpha in developing myositis.

National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-73226 (URN)10.1155/2012/637452 (DOI)22505941 (PubMedID)
Available from: 2013-06-19 Created: 2013-06-19 Last updated: 2018-06-08Bibliographically approved
2. TNF-alpha in an Overuse Muscle Model - Relationship to Muscle Fiber Necrosis/Regeneration, the NK-1 Receptor and an Occurrence of Bilateral Involvement
Open this publication in new window or tab >>TNF-alpha in an Overuse Muscle Model - Relationship to Muscle Fiber Necrosis/Regeneration, the NK-1 Receptor and an Occurrence of Bilateral Involvement
2013 (English)In: Journal Clinical & Cellular Immunology, ISSN 2155-9899, Vol. 4, no 2Article in journal (Refereed) Published
Abstract [en]

TNF-alphais known to be involved in muscle damage and inflammation (myositis). Therelationships between the TNF-alpha system and muscle fibernecrosis/regeneration and the tachykinin system in this situation are unclear.We have an experimental rabbit model related to unilateral muscle overuse whichleads to marked muscle derangement and myositis bilaterally. Using this model,staining for TNF-alpha, in parallel with staining for the substance P-preferredreceptor (NK-1R) and desmin were performed. Desmin staining was used as areference concerning identification of degeneration/regeneration and the soleusmuscle was the muscle examined. It was observed that the inflammatory cells, aswell as blood vessel walls in the myositis areas, expressed TNF-alpha mRNA.Muscle fibers that were interpreted to represent necrotic fibers expressedTNF-alpha mRNA reactions and showed NK-1R immunoreactions, the reactions beingconfined to white blood cells that had infiltrated into the fibers. Musclefibers that were interpreted to be in a regenerative state expressedpatchy/widespread TNF-alpha mRNA and point like NK-1R immunoreactions. Abnormalmuscle fibers thus showed TNF-alpha mRNA as well as NK-1R immunoreactions.Normal muscle fibers never showed these reactions. Occurrence of inflammatorycell and muscle fiber TNF-alpha mRNA reactions was equally marked in the myositisareas of the contralateral side as in these areas of the ipsilateralexperimental side. The observations show that the TNF-alpha system is muchinvolved in the processes that occur in the muscle derangement/myositisprocesses. The involvement relates to effects in processes of both regenerationand muscle fiber necrosis. It may be that substance P via activation throughthe NK-1R influences the TNF-alpha expression. The findings of TNF-alphaupregulation also for the contralateral side show that the TNF-alpha system isinvolved both ipsi and contralaterally during the development of myosits/muscleaffection in response to unilateral overuse.

Keywords
Muscle, Inflammation, Myositis, TNF-alpha, Tachykinins, Degeneration, Regeneration
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-73341 (URN)10.4172/2155-9899.1000138 (DOI)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2018-06-08Bibliographically approved
3. Bilateral muscle fiber and nerve influences by TNF-alpha in response to unilateral muscle overuse: studies on TNF receptor expressions
Open this publication in new window or tab >>Bilateral muscle fiber and nerve influences by TNF-alpha in response to unilateral muscle overuse: studies on TNF receptor expressions
2017 (English)In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 18, no 1, article id 498Article in journal (Other academic) Published
Abstract [en]

Background:

TNF-alpha is suggested to be involved in muscle damage and muscle inflammation (myositis). In order to evaluate whether TNF-alpha is involved in the myositis that occurs in response to muscle overuse, the aim was to examine the expression patterns of TNF receptors in this condition.

Methods:

A rabbit muscle overuse model leading to myositis in the soleus muscle was used. The expression patterns of the two TNF receptors Tumor Necrosis Factor Receptor type 1 (TNFR1) and Tumor Necrosis Factor Receptor type 2 (TNFR2) were investigated. In situ hybridization and immunofluorescence were utilized. Immunostainings for desmin, NK-1R and CD31 were made in parallel.

Results:

Immunoreactions (IR) for TNF receptors were clearly observed in white blood cells, fibroblasts and vessel walls, and most interestingly also in muscle fibers and nerve fascicles in the myositis muscles. There were very restricted reactions for these in the muscles of controls. The upregulation of TNF receptors was for all types of structures seen for both the experimental side and the contralateral nonexperimental side. TNF receptor expressing muscle fibers were present in myositis muscles. They can be related to attempts for reparation/regeneration, as evidenced from results of parallel stainings. Necrotic muscle fibers displayed TNFR1 mRNA and TNFR2 immunoreaction (IR) in the invading white blood cells. In myositis muscles, TNFR1 IR was observed in both axons and Schwann cells while TNFR2 IR was observed in Schwann cells. Such observations were very rarely made for control animals.

Conclusions:

The findings suggest that there is a pronounced involvement of TNF-alpha in the developing myositis process. Attempts for reparation of the muscle tissue seem to occur via both TNFR1 and TNFR2. As the myositis process also occurs in the nonexperimental side and as TNF receptors are confined to nerve fascicles bilaterally it can be asked whether TNF-alpha is involved in the spreading of the myositis process to the contralateral side via the nervous system. Taken together, the study shows that TNF-alpha is not only associated with the inflammation process but that both the muscular and nervous systems are affected and that this occurs both on experimental and nonexperimental sides.

Keywords
TNF-alpha, Myositis, Muscle, TNFR1, TNFR2, nerve structures
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-141941 (URN)10.1186/s12891-017-1796-6 (DOI)000416424300005 ()29183282 (PubMedID)
Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2018-06-09Bibliographically approved
4. Marked expression of TNF receptors in human peritendinous tissues including in nerve fascicles with axonal damage: Studies on tendinopathy and tennis elbow
Open this publication in new window or tab >>Marked expression of TNF receptors in human peritendinous tissues including in nerve fascicles with axonal damage: Studies on tendinopathy and tennis elbow
2017 (English)In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 17, no 3, p. 226-236Article in journal (Refereed) Published
Abstract [en]

Background: The peritendinous connective tissues can have importance in chronic tendon pain. Recently cytokine TNF-alpha has been suggested to be involved in tendinopathic processes. It is not known how TNF-alpha and its receptors TNFR1 and TNFR2 are expressed in peritendinous tissues.

Methods: The objective for this study was to immunohistochemically evaluate the expression patterns of these in the peritendinous tissue located between the plantaris and Achilles tendons and the one located superficially to the extensor origin at the elbow region for patients with tendinopathy/tennis elbow.

Results: The nerve fascicles were of two types, one type being homogenously stained for the nerve markers beta III-tubulin and neurofilament and the other showing deficits for these suggesting features of axonal damage. Much more distinct TNFR1/TNFR2 immunoreactions were seen for the latter nerve fascicles. TNFR1 was seen in axons, TNFR2 mainly in Schwann cells. TNFR1 and particularly TNFR2 were seen in walls of parts of blood vessels. The dispersed cells showed frequently TNFR1 and TNFR2 immunoreactivity.

Discussion: These findings suggest that TNF-alpha can be related to degenerative events but also attempts for healing concerning the nerve structures. The marked expression of the TNF-alpha system in the peritendinous tissue suggests an impact of TNF-alpha in tendinopathy/tennis elbow.

Place, publisher, year, edition, pages
JMNI, 2017
Keywords
TNF, Peritendinous, Tendinopathy, Tennis Elbow, Nerve Degeneration
National Category
Neurosciences Physiology
Identifiers
urn:nbn:se:umu:diva-140056 (URN)000410545600012 ()28860425 (PubMedID)
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2018-06-09Bibliographically approved

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