Key indicators of repetitive overuse-induced neuromuscular inflammation and fibrosis are prevented by manual therapy in a rat model

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Abstract

Background

We examined the effectiveness of a manual therapy consisting of forearm skin rolling, muscle mobilization, and upper extremity traction as a preventive treatment for rats performing an intensive lever-pulling task. We hypothesized that this treatment would reduce task-induced neuromuscular and tendon inflammation, fibrosis, and sensorimotor declines.

Methods

Sprague-Dawley rats performed a reaching and lever pulling task for a food reward, 2 h/day, 3 days/week, for 12 weeks, while simultaneously receiving the manual therapy treatment 3 times per week for 12 weeks to either the task-involved upper extremities (TASK-Tx), or the lower extremities as an active control group (TASK-Ac). Results were compared to similarly treated control rats (C-Tx and C-Ac).

Results

Median nerves and forearm flexor muscles and tendons of TASK-Ac rats showed higher numbers of inflammatory CD68+ and fibrogenic CD206+ macrophages, particularly in epineurium, endomysium and epitendons than TASK-Tx rats. CD68+ and CD206+ macrophages numbers in TASK-Tx rats were comparable to the non-task control groups. TASK-Ac rats had more extraneural fibrosis in median nerves, pro-collagen type I levels and immunoexpression in flexor digitorum muscles, and fibrogenic changes in flexor digitorum epitendons, than TASK-Tx rats (which showed comparable responses as control groups). TASK-Ac rats showed cold temperature, lower reflexive grip strength, and task avoidance, responses not seen in TASK-Tx rats (which showed comparable responses as the control groups).

Conclusions

Manual therapy of forelimbs involved in performing the reaching and grasping task prevented the development of inflammatory and fibrogenic changes in forearm nerves, muscle, and tendons, and sensorimotor declines.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12891-021-04270-0.

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The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.

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Regulatory interactions between muscle and the immune system during muscle regeneration.

James G. Tidball, S Villalta (2010)

Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.

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Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair.

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Certain macrophage phenotypes contribute to tissue fibrosis, but why? Tissues host resident mononuclear phagocytes for their support to maintain homeostasis. Upon injury the changing tissue microenvironment alters their phenotype and primes infiltrating monocytes toward pro-inflammatory macrophages. Several mechanisms contribute to their deactivation and macrophage priming toward anti-inflammatory and pro-regenerative macrophages that produce multiple cytokines that display immunosuppressive as well as pro-regeneratory effects, such as IL-10 and TGF-beta1. Insufficient parenchymal repair creates a tissue microenvironment that becomes dominated by multiple growth factors that promote the pro-fibrotic macrophage phenotype that itself produces large amounts of such growth factors that further support fibrogenesis. However, the contribution of resident mononuclear phagocytes to physiological extracellular matrix turnover implies also their fibrolytic effects in the late stage of tissue scaring. Fibrolytic macrophages break down fibrous tissue, but their phenotypic characteristics remain to be described in more detail. Together, macrophages contribute to tissue fibrosis because the changing tissue environments prime them to assist and orchestrate all phases of tissue injury and repair. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Copyright © 2012 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Mary F. Barbe:

ORCID: https://orcid.org/0000-0002-5235-9803

mary.barbe@temple.edu

Michele Y. Harris: micheleh@temple.edu

Geneva E. Cruz: geneva.cruz@temple.edu

Mamta Amin: mamta@temple.edu

Nathan M. Billett: tuj16871@temple.edu

Jocelynne T. Dorotan: JTD64@pitt.edu

Emily P. Day: tug78253@temple.edu

Seung Y. Kim: tug27380@temple.edu

Geoffrey M. Bove: geoffreybove@gmail.com

Journal

Journal ID (nlm-ta): BMC Musculoskelet Disord

Journal ID (iso-abbrev): BMC Musculoskelet Disord

Title: BMC Musculoskeletal Disorders

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2474

Publication date (Electronic): 5 May 2021

Publication date PMC-release: 5 May 2021

Publication date Collection: 2021

Volume: 22

Electronic Location Identifier: 417

Affiliations

[1 ]GRID grid.264727.2, ISNI 0000 0001 2248 3398, Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, , Temple University, ; 3500 North Broad Street, Philadelphia, PA 19140 USA

[2 ]Bove Consulting, Kennebunkport, ME 04046 USA

Author information

Mary F. Barbe https://orcid.org/0000-0002-5235-9803

Article

Publisher ID: 4270

DOI: 10.1186/s12891-021-04270-0

PMC ID: 8101118

PubMed ID: 33952219

SO-VID: be097a31-e838-4313-9ecb-33a5a23cf17c

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 November 2020

Date accepted : 7 April 2021

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: overuse injury,work-related musculoskeletal disorders,nerve,muscle,tendon,massage therapy

Data availability:

ScienceOpen disciplines: Orthopedics

Keywords: overuse injury, work-related musculoskeletal disorders, nerve, muscle, tendon, massage therapy

Key indicators of repetitive overuse-induced neuromuscular inflammation and fibrosis are prevented by manual therapy in a rat model

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Most cited references 85

Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Regulatory interactions between muscle and the immune system during muscle regeneration.

Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair.

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