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Cross transfer effects after unilateral muscle overuse: an experimental animal study about alterations in the morphology and the tachykinin system of muscles
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). (muskelgruppen)
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Unilateral exercise can produce certain contralateral strength effects. Deleterious events can be cross-transferred as well, as illustrated by a strict symmetry in some chronic inflammatory diseases. To date, knowledge on the effects of marked overuse of skeletal muscles is limited, and there is largely no information if unilateral overuse affects the contralateral muscles. In view of this, the present study was undertaken to test the hypothesis that unilateral muscle overuse causes alterations in tissue structure and the tachykinin system, with a focus on substance P (SP), not only in the exercised muscles, but also in the contralateral muscles. SP is a well-known neuromodulator that is known to be proinflammatory.

An experimental rabbit model with unilateral muscle overuse of the soleus and gastrocnemius muscles caused by exercise via electrical muscle stimulation (E/EMS) was used. In total, 40 rabbits were randomly divided into seven groups of which two groups served as controls. The rabbits were anaesthetized and then set on a “kicking machine” to perform exercise via EMS for 2h every second day. Experimental periods for groups 1-3 were 1, 3 and 6w, respectively, whereas groups 4-6 were exercised for 1w but also subjected to injections in the peritendinous tissue with SP, NaCL, Captopril (C), an ACE inhibitor, and DL-Thiorphan (Th) which inhibits the activity of neural endopeptidase. One group was not subjected to the experiment at all. The day after the last session of E/EMS, the soleus muscle and the gastrocnemius muscle from both legs were collected for analysis. Alterations in muscle structure and the tachykinin system were analyzed with enzyme and immunohistochemical techniques, in situ hybridization and EIA methods.

After 1w of E/EMS, focal areas of the exercised muscles contained a mild infiltration of inflammatory cells (myositis) and small morphological changes. After 3 and 6w of E/EMS, distinct myositis and muscle changes were bilaterally present in focal areas of both muscles. The structural changes, which mainly were observed in myositis areas, consisted of increased fiber size variability, split fibers, internal myonuclei, necrotic fibers, fibrosis, fat infiltration, and small fibers containing developmental MyHCs. Bilateral morphological changes, such as loss of axons, were also observed in nerves. In addition, expressions of tachykinin and the SP-preferred receptor, the neurokinin-1 (NK-1R), were bilaterally upregulated in nerve structures and blood vessel walls.  Infiltrating white blood cells exhibited tachykinin–like and NK-1R immunoreactivity. NK-1R immunoreactions were also found in necrotic and regenerating muscle fibers.

The concentration of tachykinin (SP) was significantly increased in both soleus and gastrocnemius muscles after E/EMS. There was a significant correlation between the two sides in concentration of tachykinin and in the intensity of tachykinin-like immunoreaction in blood vessel walls. The muscle fiber size and capillary supply of fibers were bilaterally decreased after 3w of EMS. The myositis areas contained an increased number of vessels with a larger size than capillaries, while areas with increased amount of connective tissue contained a very low number of capillaries. A bilateral fiber type shift against a lower proportion of slow MyHCI fibers and higher proportion of fast MyHCII fibers was observed in both muscles. The local injections of C+Th and SP+C+Th led to marked structural changes in the muscle tissue and marked increased NK-1R and tachykinin-like immunoreactivity in the myositis areas and increased tachykinin concentration in the tissue.

In conclusion, the repetitive unilateral muscle overuse caused by E/EMS led overtime to muscle injury and myositis. The affected areas contained both degenerative and regenerative alterations in the muscle tissue and nerves, and an upregulation of the tachykinin system. Most interestingly, the changes not only occurred in the exercised side, but also in the homologous contralateral muscles. The tachykinin system appears to be an important factor in the processes of crossover effects. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 73 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1581
Keyword [en]
Triceps surae, overuse, contralateral, muscle, muscle fiber, MyHC, capillary, tachykinin, substance P, NK-1R, inflammation
National Category
Sport and Fitness Sciences Physiology
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-71242ISBN: 978-91-7459-636-6 (print)ISBN: 978-91-7459-635-9 (print)OAI: oai:DiVA.org:umu-71242DiVA: diva2:622901
Public defence
2013-06-14, N320, Naturvetarhuset, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2013-05-23 Last updated: 2013-05-24Bibliographically approved
List of papers
1. Marked effects of tachykinin in myositis both in the experimental side and contralaterally: studies on NK-1 receptor expressions in an animal model
Open this publication in new window or tab >>Marked effects of tachykinin in myositis both in the experimental side and contralaterally: studies on NK-1 receptor expressions in an animal model
2013 (English)In: ISRN Inflammation, ISSN 2090-8695, Vol. 2013, no 907821Article in journal (Refereed) Published
Abstract [en]

Muscle injury and inflammation (myositis) in a rabbit model of an unilateral muscle overuse were examined. It is unknown if the tachykinin system has a functional role in this situation. In this study, therefore, the neurokinin-1 receptor (NK-1R) expression patterns were evaluated. White blood cells, nerve fascicles, fine nerve fibers, and blood vessel walls in myositis areas showed NK-1R immunoreaction. NK-1R mRNA reactions were observable for white blood cells and blood vessel walls of these areas. NK-1R immunoreaction and NK-1R mRNA reactions were also seen for muscle fibers showing degenerative and regenerative features. There were almost no NK-1R immunoreactions in normal muscle tissue. Interestingly, marked NK-1R expressions were seen for myositis areas of both the experimental side and the contralateral nonexperimental side. EIA analyses showed that the concentration of substance P in the muscle tissue was clearly increased bilaterally at the experimental end stage, as compared to the situation for normal muscle tissue. These observations show that the tachykinin system is very much involved in the processes that occur in muscle injury/myositis. The effects can be related to proinflammatory effects and/or tissue repair. The fact that there are also marked NK-1R expressions contralaterally indicate that the tachykinin system has crossover effects.

National Category
Cell and Molecular Biology Sport and Fitness Sciences
Identifiers
urn:nbn:se:umu:diva-68846 (URN)10.1155/2013/907821 (DOI)24049666 (PubMedID)
Available from: 2013-04-26 Created: 2013-04-26 Last updated: 2017-12-06Bibliographically approved
2. Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis
Open this publication in new window or tab >>Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis
2013 (English)In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 14, 134- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Tachykinins can have pro-inflammatory as well as healing effects during tissue reorganization and inflammation. Recent studies report an up-regulation in the expression of the substance P (SP)-preferred receptor, the neurokinin-1 receptor, in marked muscle inflammation (myositis). There is, however, only very little information on the expression patterns and levels of tachykinins in this situation.

METHODS: The tachykinin system was analyzed using a rabbit experimental model of muscle overuse, whereby unilateral muscle exercise in combination with electrical stimulation led to muscle derangement and myositis in the triceps surae muscle (experimental length 1--6 weeks). Evaluations were made for both parts of the muscle (soleus and gastrocnemius muscles) in experimental and non-experimental (contralateral) sides. Morphologic evaluation, immunohistochemistry, in situ hybridization and enzyme immunoassay (EIA) analyses were applied.

RESULTS: Myositis and muscle derangement occurred focally not only in the experimental side but also in the non-experimental side. In the inflammatory areas (focal myositis areas), there were frequent nerve fibers showing tachykinin-like immunoreactivity and which were parts of nerve fascicles and which were freely dispersed in the tissue. Cells in the inflammatory infiltrates showed tachykinin-like immunoreactivity and tachykinin mRNA expression. Specific immunoreactivity and mRNA expression were noted in blood vessel walls of both sides, especially in focally affected areas. With increasing experimental length, we observed an increase in the degree of immunoreactivity in the vessel walls. The EIA analyses showed that the concentration of tachykinin in the tissue on both sides increased in a time-dependent manner. There was a statistical correlation in the concentration of tachykinin and the level of tachykinin immunoreactivity in the blood vessel walls between experimental and non-experimental sides.

CONCLUSIONS: The observations show an up-regulation of the tachykinin system bilaterally during muscle derangement/myositis in response to pronounced unilateral muscle overuse. This up-regulation occurred in inflammatory areas and was related not only to increased tachykinin innervation but also to tachykinin expression in blood vessel walls and inflammatory cells. Importantly, the tachykinin system appears to be an important factor not only ipsilaterally but also contralaterally in these processes.

Keyword
Muscle, Triceps surae, Muscle overuse, Myositis, Inflammation, Tachykinin, Substance P
National Category
Sport and Fitness Sciences Health Care Service and Management, Health Policy and Services and Health Economy
Identifiers
urn:nbn:se:umu:diva-68822 (URN)10.1186/1471-2474-14-134 (DOI)23587295 (PubMedID)
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2017-12-06Bibliographically approved
3. Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise
Open this publication in new window or tab >>Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, e52230- p.Article in journal (Refereed) Published
Abstract [en]

It is well established that unilateral exercise can produce contralateral effects. However, it is unclear whether unilateral exercise that leads to muscle injury and inflammation also affects the homologous contralateral muscles. To test the hypothesis that unilateral muscle injury causes contralateral muscle changes, an experimental rabbit model with unilateral muscle overuse caused by a combination of electrical muscle stimulation and exercise (EMS/E) was used. The soleus and gastrocnemius muscles of both exercised and non-exercised legs were analyzed with enzyme-and immunohistochemical methods after 1, 3 and 6 weeks of repeated EMS/E. After 1 w of unilateral EMS/E there were structural muscle changes such as increased variability in fiber size, fiber splitting, internal myonuclei, necrotic fibers, expression of developmental MyHCs, fibrosis and inflammation in the exercised soleus muscle. Only limited changes were found in the exercised gastrocnemius muscle and in both non-exercised contralateral muscles. After 3 w of EMS/E, muscle fiber changes, presence of developmental MyHCs, inflammation, fibrosis and affections of nerve axons and AChE production were observed bilaterally in both the soleus and gastrocnemius muscles. At 6 w of EMS/E, the severity of these changes significantly increased in the soleus muscles and infiltration of fat was observed bilaterally in both the soleus and the gastrocnemius muscles. The affections of the muscles were in all three experimental groups restricted to focal regions of the muscle samples. We conclude that repetitive unilateral muscle overuse caused by EMS/E overtime leads to both degenerative and regenerative tissue changes and myositis not only in the exercised muscles, but also in the homologous non-exercised muscles of the contralateral leg. Although the mechanism behind the contralateral changes is unclear, we suggest that the nervous system is involved in the cross-transfer effects.

Place, publisher, year, edition, pages
Public Library Science, 2012
National Category
Sport and Fitness Sciences
Identifiers
urn:nbn:se:umu:diva-64452 (URN)10.1371/journal.pone.0052230 (DOI)000312794500120 ()
Available from: 2013-02-05 Created: 2013-01-29 Last updated: 2017-12-06Bibliographically approved
4. Unilateral muscle overuse causes bilateral changes in muscle fibre composition and vascular supply
Open this publication in new window or tab >>Unilateral muscle overuse causes bilateral changes in muscle fibre composition and vascular supply
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Sport and Fitness Sciences Physiology
Identifiers
urn:nbn:se:umu:diva-71281 (URN)
Available from: 2013-05-24 Created: 2013-05-24 Last updated: 2015-01-20
5. Experimental studies favour that tachykinins are involved in the process of myositis and muscle derangement in an overuse animal model
Open this publication in new window or tab >>Experimental studies favour that tachykinins are involved in the process of myositis and muscle derangement in an overuse animal model
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Sport and Fitness Sciences Physiology
Identifiers
urn:nbn:se:umu:diva-71282 (URN)
Available from: 2013-05-24 Created: 2013-05-24 Last updated: 2013-05-24Bibliographically approved

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