Tissue stretch decreases soluble TGF‐β1 and type‐1 procollagen in mouse subcutaneous connective tissue: Evidence from ex vivo and in vivo models

Department of Neurology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Journal of Cellular Physiology (Impact Factor: 3.84). 02/2008; 214(2):389-95. DOI: 10.1002/jcp.21209
Source: PubMed


Transforming growth factor beta 1 (TGF-beta1) plays a key role in connective tissue remodeling, scarring, and fibrosis. The effects of mechanical forces on TGF-beta1 and collagen deposition are not well understood. We tested the hypothesis that brief (10 min) static tissue stretch attenuates TGF-beta1-mediated new collagen deposition in response to injury. We used two different models: (1) an ex vivo model in which excised mouse subcutaneous tissue (N = 44 animals) was kept in organ culture for 4 days and either stretched (20% strain for 10 min 1 day after excision) or not stretched; culture media was assayed by ELISA for TGF-beta1; (2) an in vivo model in which mice (N = 22 animals) underwent unilateral subcutaneous microsurgical injury on the back, then were randomized to stretch (20-30% strain for 10 min twice a day for 7 days) or no stretch; subcutaneous tissues of the back were immunohistochemically stained for Type-1 procollagen. In the ex vivo model, TGF-beta1 protein was lower in stretched versus non-stretched tissue (repeated measures ANOVA, P < 0.01). In the in vivo model, microinjury resulted in a significant increase in Type-1 procollagen in the absence of stretch (P < 0.001), but not in the presence of stretch (P = 0.21). Thus, brief tissue stretch attenuated the increase in both soluble TGF-beta1 (ex vivo) and Type-1 procollagen (in vivo) following tissue injury. These results have potential relevance to the mechanisms of treatments applying brief mechanical stretch to tissues (e.g., physical therapy, respiratory therapy, mechanical ventilation, massage, yoga, acupuncture).

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Available from: Sheryl White, Oct 10, 2015
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    • "Over the last decade, a series of studies have shown that, at least with needle manipulation during manual acupuncture, connective tissue elements wrap around the needle to increase tension as the needle is rotated and to cause tissue deformation (Davis, Churchill, Badger, Dunn, & Langevin, 2012; Langevin et al., 2011). This grabbing of collagen and other subcutaneous tissue components appears to stimulate fibrocytes and other local tissue elements to activate cytokines and release chemicals that could function in local responses to acupuncture (Bouffard et al., 2008; Goldman et al., 2010). One local chemical is adenosine, which is released during acupuncture to reduce experimental pain in rodents (Goldman et al., 2010). "
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    ABSTRACT: Although mechanisms underlying acupuncture regulation of pain have been studied by a number of laboratories in many countries, much less is known about its ability to modulate cardiovascular function. In the last two decades, our laboratory has systematically investigated the peripheral and central neural mechanisms underlying acupuncture regulation of blood pressure. These observations account for acupuncture's distant actions and, to some extent, its local actions, with respect to the site of needling. Four fundamental findings have advanced our knowledge. First, point-specific effects of acupuncture underlie its cardiovascular actions. Second, variable regions in the supraspinal and spinal central nervous system that receive input from somatic afferent stimulation account for acupuncture's ability to modulate blood pressure. Thus, depending on the underlying situation, for example, high or low blood pressure, acupuncture modifies autonomic outflow by reducing activity in brain stem nuclei that participate in the primary response. Third, repetitive acupuncture through a molecular mechanism can cause prolonged cardiovascular effects that far outlast acupuncture stimulation. Fourth, there is a range of cardiovascular responsiveness to acupuncture that depends, at least in part, on interactions between neural modulators that synaptically regulate autonomic function in the brain stem. Thus, acupuncture has the capability of profoundly regulating cardiovascular function in patients with disease, for example, hypertension, and the experimental laboratory is directing best approaches to study its actions in humans.
    International Review of Neurobiology 11/2013; 111:257-71. DOI:10.1016/B978-0-12-411545-3.00013-4 · 1.92 Impact Factor
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    • "A rodent study using in vivo as well as ex vivo examination of a 10 minute static stretch application showed that this stretch attenuated the increase in both soluble TGF-β1 (ex vivo) and type-1 procollagen (in vivo) following tissue injury. The investigators interpreted this as an indication for a potential anti-fibrotic effect of static stretching (70). A subsequent in vivo study by the same group, also conducted with rodents, showed that a yogalike stretch application of 10 minutes – conducted twice a day over a period of 12 days – clearly decreased the inflammatory responses induced by previous injection of carragean into the subcutaneous connective tissues. "
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    ABSTRACT: Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical, humoral and cellular factors. Originating from vulnerable myofibres, muscle cell necrosis and inflammatory processes are present in DMD. Muscular recovery is limited due to the limited number and capacity of satellite cells. Hence, a proactive and multimodal approach is necessary in order to activate protective mechanisms and to hinder catabolic and tissue degrading pathways. Several avenues are discussed in terms of potential antifibrotic therapy approaches. These include pharmaceutical, nutritional, exercise-based and other mechanostimulatory modalities (such as massage or yoga-like stretching) with the intention of exerting an anti-inflammatory and antifibrotic effect on the affected muscular tissues. A preventive intervention at an early age is crucial, based on the early and seemingly non-reversible nature of the fibrotic tissue changes. Since consistent assessment is essential, different measurement technologies are discussed.
    Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 12/2012; 31(3):184-95.
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    • "In addition to its potential role in chronic pain, an important characteristic of connective tissue is its responsiveness to mechanical stimulation [17], [18]. In particular, recent evidence suggests that low amplitude static (non-cyclical) stretching may have beneficial antifibrotic [19] and antiflammatory effects [20]. The goal of this study was to investigate whether gentle stretching of tissue in vivo could reduce inflammation within the connective tissues of the low back. "
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    ABSTRACT: The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.
    PLoS ONE 01/2012; 7(1):e29831. DOI:10.1371/journal.pone.0029831 · 3.23 Impact Factor
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