Tissue Stretch Decreases Soluble TGF-β1 and Type-1 Procollagen in Mouse Subcutaneous Connective Tissue: Evidence From Ex Vivo and In Vivo Models

Svært interessant studie som viser at å strekke bindevev jevnlig, f.eks. slik vi gjør under behandling eller i yoga, gjør at vi får mindre arrvev. Det produseres mindre TGF-B1, et molekyl som stimulerer arrvevproduksjon. Spesielt for indre organer er dette hjelpsomt, som lunger og tarmer, f.eks. etter operasjoner eller ved betennelsesykdommer. Forskerene viser at det holder å strekke overkroppen så det blir 20-30% lengre avstand mellom hofte og skulder. Dette får vi til med noe så enkelt som å  svaie ryggen og strekke armene opp. F.eks.  ved å ligge på ryggen over en ball eller gjøre The Founder.


We tested the hypothesis that brief (10 min) static tissue stretch attenuates TGF-β1-mediated new collagen deposition in response to injury.

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-β1 (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).

Transforming growth factor β1 (TGF-β1) is well-established as one of the key cytokines regulating the response of fibroblasts to injury, as well as the pathological production of fibrosis (Barnard et al., 1990;Sporn and Roberts, 1990; Leask and Abraham, 2004). Tissue injury is known to cause auto-induction of TGF-β1 protein production and secretion (Van Obberghen-Schilling et al., 1988; Morgan et al., 2000). Elevated extracellular levels of TGF-β1 have a major impact on extracellular matrix composition by causing autocrine and paracrine activation of fibroblast cell surface receptors, leading to increased synthesis of collagens, elastin, proteoglycans, fibronectin, and tenascin (Balza et al., 1988; Bassols and Massague, 1988; Kahari et al., 1992; Cutroneo, 2003).

In vivo, connective tissue remodeling is not limited to tissue injury, but also occurs in response to changing levels of tissue mechanical forces (e.g., immobilization, beginning a new exercise or occupation). Long-standing physical therapy practices also suggest that externally applied mechanical forces can be used to reduce collagen deposition during tissue repair and scar formation (Cummings and Tillman, 1992).

In the stretch group, the mice underwent stretching of the trunk for 10 min twice a day for 7 days in the following manner: each mouse was suspended by the tail such that its paws barely touched a surface slightly inclined relative to the vertical. In response to this maneuver, the mouse spontaneously extended its front and hind limbs (Fig. 1B) with the distance between ipsilateral hip and shoulder joints becoming 20–30% greater than the resting distance.


B: Method used to induce tissue stretch in vivo. Mice are suspended by the tail such that their paws barely touch a surface slightly inclined relative to the vertical. The mice spontaneously extend their front and hind limbs, the distance between ipsilateral hip and shoulder joints becoming 20–30% greater than the resting distance.

Effect of tissue stretch on TGF-β1 protein ex vivo. A: Time course of TGF-β1 protein levels in the culture media for non-stretched (closed circle, N = 4) and stretched (open circle, N = 4) mouse subcutaneous tissue explants on days 0, 1, and 3 post-stretch (or no stretch). All tissue samples were excised and incubated for 24h prior to day 0.B:Levels of TGF-β1 protein in the culture media at day 3 for non-stretched and stretched sbcutaneous tissue samples (N = 36). Asterisk (*) indicates significant difference from stretched (P = 0.002). Error bars represent standard errors.

Ex vivo tissue injury and cell viability assessment. A: Time course of LDH concentration in the culture media (marker of cell death) for non-stretched (closed circle, n = 4) and stretched (open circle, n = 4) mouse subcutaneous tissue explants on days 0, 1, and 3 post-stretch (or no stretch). B,C: Confocal microscopy imaging of mouse subcutaneous tissue explants showing similar proportions of live (green) and dead (red) cells in non-stretched (A) versus stretched (B) tissue after 3 day incubation post-stretch (or no stretch). Images are projections of three-dimensional image stacks. Scale bars: 40 μm.

Effect of tissue stretch in vivo on subcutaneous tissue Type-1 procollagen in mouse microinjury model. A: Mean ± SE procollagen percent staining area in non-injured versus injured sides, without stretch (N = 11) and with stretch (N = 10); B,C: Type-1 procollagen in non-stretched and stretched tissue (both injured). Scale bars, 40 μm.

First, stretching mouse subcutaneous tissue explants by 20% for 10 min decreases soluble TGF-β1 levels measured 3 days after stretch. During the 4-day incubation, TGF-β1 levels in the culture media increase in both stretched and non-stretched samples; because some tissue trauma occurs at the time of excision, this progressive rise in TGF-β1 is consistent with an injury response. However, the increase in the level of TGF-β1 is slower in the samples that are briefly stretched for 10 min, compared with samples that are not stretched. Since TGF-β1 auto-induction is an important mechanism driving the increase in collagen synthesis following tissue injury (Cutroneo, 2003), we hypothesized that brief stretching of tissue following injury in vivo would decrease soluble TGF-β1 levels, attenuate TGF-β1 auto-induction and decrease new collagen deposition.

Testing this hypothesis in a mouse subcutaneous tissue injury model showed that elongating the tissues of the trunk by 20–30% for 10 min twice a day significantly reduces the amount of subcutaneous new collagen 7 days following subcutaneous tissue injury.

Reducing scar and adhesion formation using stretch and mobilization is especially important for internal tissue injuries and inflammation involving fascia and organs, as opposed to open wounds. For open wounds (including surgical incisions) and severe internal tears (such as a ruptured ligament or tendon), wound closure and strength are critical and thus a certain amount of scarring is necessary and inevitable. In the case of minor sprains and repetitive motion injuries, however, scarring is mostly detrimental since it can contribute to maintaining the chronicity of tissue stiffness, abnormal movement patterns, and pain (Langevin and Sherman, 2007).

We have proposed that therapies that briefly stretch tissues beyond the habitual range of motion (physical therapy, massage, yoga, acupuncture) locally inhibit new collagen formation for several days after stretch and thus prevent and/or ameliorate soft tissue adhesions (Langevin et al., 2001, 2002, 2005, 2006a, 2007).

Proposed model for healing of connective tissue injury in the absence (A,C,E) and presence (B,D,F) of tissue stretch. In this model, brief stretching of tissue beyond the habitual range of motion reduces soluble TGF-β1 levels (D) causing a decrease in the fibrotic response, less collagen deposition, and reduced tissue adhesion (F) compared with no stretch (E). Black lines represent newly formed collagen.

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