scholarly journals Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on Secreted frizzled-related protein 2)

2016 ◽  
Vol 48 (6) ◽  
pp. 397-408 ◽  
Author(s):  
Uğur Akpulat ◽  
İlyas Onbaşılar ◽  
Y. Çetin Kocaefe
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Fatty Infiltration ◽  
Muscle Fibrosis ◽  
Clear Cut ◽  
Extracellular Matrix Components ◽  
Transcriptional Changes ◽  
Slow Twitch Fibers ◽  
Skeletal Muscle Fibrosis

The pathological endpoint of congenital and senile myopathies is chronic muscle degeneration characterized by the atrophy of contractile elements, accompanied by fibrosis and fatty infiltration of the interstitium. Tenotomy is the release of preload that causes abrupt shortening of the muscle and models atrophy and fibrosis without prominent inflammatory response. Fibrosis in the skeletal muscle is known to be triggered by transforming growth factor (TGF)-β, which is activated by inflammatory events. As these were lacking, tenotomy provided an opportunity to investigate transcriptional events on a background without inflammation. An unbiased look at the transcriptome of tenotomy-immobilized soleus muscle revealed that the majority of the transcriptional changes took place in the first 4 wk. Regarding atrophy, proteasomal and lysosomal pathways were actively involved in accompanying cathepsins and calpains in the breakdown of the macromolecular contractile machinery. The transcriptome provided clear-cut evidence for the upregulation of collagens and several extracellular matrix components that define fibrotic remodeling of the skeletal muscle architecture as well as activation of the fibro-adipogenic precursors. Concomitantly, Sfrp2, a Wnt antagonist as well as a procollagen processor, accompanied fibrosis in skeletal muscle with an expression that was stringently confined to the slow-twitch fibers. An interpreted mechanistic scenario construed the kinetic events initiated through the abnormal shortening of the muscle fibers as enough to trigger the resident latent TGF-β in the extracellular matrix, leading to the activation of fibroadipogenic precursors. As in the heart, Sfrp2 shows itself to be a therapeutic target for the prevention of irreversible fibrosis in degenerative skeletal muscle conditions.

scholarly journals The Combination of Electroacupuncture and Massage Therapy Alleviates Myofibroblast Transdifferentiation and Extracellular Matrix Production in Blunt Trauma-Induced Skeletal Muscle Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Na Zhao ◽  
Bo Liu ◽  
Si-Wen Liu ◽  
Wei Zhang ◽  
Hua-Nan Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Growth Factor ◽  
Blunt Trauma ◽  
Massage Therapy ◽  
Muscle Fibrosis ◽  
Extracellular Matrix Production ◽  
Matrix Production ◽  
Skeletal Muscle Fibrosis ◽  
Tgf Β1

Complementary therapies, such as acupuncture and massage, had been previously reported to have therapeutic effects on skeletal muscle contusions. However, the recovery mechanisms on skeletal muscles after blunt trauma via the combination of electroacupuncture (EA) and massage therapy remain unclear. In the present study, a rat model of the skeletal muscle fibrosis following blunt trauma to rat skeletal muscle was established, and the potential molecular mechanisms of EA + massage therapy on the skeletal muscle fibrosis were investigated. The results suggested that EA + massage therapy could significantly decrease inflammatory cells infiltration and collagenous fiber content and ameliorate the disarrangement of sarcomeres within myofibrils compared to the model group. Further analysis revealed that EA + massage therapy could reduce the degree of fibrosis and increase the degree of myofibroblast apoptosis by downregulating the mRNA and protein expression of transforming growth factor- (TGF-) β1 and connective tissue growth factor (CTGF). Furthermore, the fibrosis of injured skeletal muscle was inhibited after treatment through the normalization of balance between matrix metalloproteinase- (MMP-) 1 and tissue inhibitor of matrix metalloproteinase (TIMP). These findings suggested that the combination of electroacupuncture and massage therapy could alleviate the fibrotic process by regulating TGF β1-CTGF-induced myofibroblast transdifferentiation and MMP-1/TIMP-1 balance for extracellular matrix production.

scholarly journals Adipose-Derived Stem Cells Alleviate Radiation-Induced Muscular Fibrosis by Suppressing the Expression of TGF-β1

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Sun ◽  
Xinchu Ni ◽  
Suping Sun ◽  
Leiming Cai ◽  
Jingping Yu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Transforming Growth Factor ◽  
Adipose Derived Stem Cells ◽  
Peripheral Tissues ◽  
Muscle Fibrosis ◽  
Muscle Tissues ◽  
Radiation Induced ◽  
Skeletal Muscle Fibrosis ◽  
Tgf Β1

We aim to investigate the effects of adipose-derived stem cells (ASCs) transplantation on irradiation-induced skeletal muscle fibrosis. Sixty-four rabbits were randomly divided into ASCs group and PBS group followed by irradiation at unilateral hip with a single dose of 80 Gy. Nonirradiated side with normal skeletal muscle served as normal control. Skeletal muscle tissues were collected from eight rabbits in each group at 1 w, 4 w, 8 w, and 26 w after irradiation. Migration of ASCs was observed in the peripheral tissues along the needle passage in the injured muscle. The proportion of the area of collagen fibers to the total area in sections of ASCs group was lower than those of PBS groups at 4 w, 8 w, and 26 w after irradiation. Significant decrease was noted in the integrated optimal density of the transforming growth factorβ1 (TGF-β1) in the ASCs group compared with those of PBS group at 4 w, 8 w, and 26 w after irradiation. Moreover, the expression of TGF-β1 was lower in the ASCs group compared to those of the PBS group at each time point determined by Western blot analysis. ASCs transplantation could alleviate irradiation fibrosis by suppressing the level of TGF-β1 in the irradiated skeletal muscle.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 4. Structural and functional consequences of skeletal muscle fibrosis

2013 ◽  
Vol 305 (3) ◽  
pp. C241-C252 ◽  
Author(s):  
Richard L. Lieber ◽  
Samuel R. Ward
Keyword(s):  
Skeletal Muscle ◽  
Structural Model ◽  
Transforming Growth Factor ◽  
Clinical Problem ◽  
Transforming Growth Factor Β ◽  
Common Mechanism ◽  
Cellular Mechanisms ◽  
Muscle Fibrosis ◽  
Activated Fibroblasts ◽  
Skeletal Muscle Fibrosis

Skeletal muscle fibrosis can be a devastating clinical problem that arises from many causes, including primary skeletal muscle tissue diseases, as seen in the muscular dystrophies, or it can be secondary to events that include trauma to muscle or brain injury. The cellular source of activated fibroblasts (myofibroblasts) may include resident fibroblasts, adult muscle stem cells, or inflammatory or perivascular cells, depending on the model studied. Even though it is likely that there is no single source for all myofibroblasts, a common mechanism for the production of fibrosis is via the transforming growth factor-β/phosphorylated Smad3 pathway. This pathway and its downstream targets thus provide loci for antifibrotic therapies, as do methods for blocking the transdifferentiation of progenitors into activated fibroblasts. A structural model for the extracellular collagen network of skeletal muscle is needed so that measurements of collagen content, morphology, and gene expression can be related to mechanical properties. Approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal muscle.

scholarly journals Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review

2019 ◽  
Vol 20 (10) ◽  
pp. 2446 ◽  
Author(s):  
Ahmed Ismaeel ◽  
Jeong-Su Kim ◽  
Jeffrey S. Kirk ◽  
Robert S. Smith ◽  
William T. Bohannon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Muscle Fibrosis ◽  
Cellular Processes ◽  
Targeted Treatments ◽  
Skeletal Muscle Fibrosis

Transforming growth factor-beta (TGF-β) isoforms are cytokines involved in a variety of cellular processes, including myofiber repair and regulation of connective tissue formation. Activation of the TGF-β pathway contributes to pathologic fibrosis in most organs. Here, we have focused on examining the evidence demonstrating the involvement of TGF-β in the fibrosis of skeletal muscle particularly. The TGF-β pathway plays a role in different skeletal muscle myopathies, and TGF-β signaling is highly induced in these diseases. In this review, we discuss different molecular mechanisms of TGF-β-mediated skeletal muscle fibrosis and highlight different TGF-β-targeted treatments that target these relevant pathways.

Regulation of mesenchymal extracellular matrix protein synthesis by transforming growth factor-beta and glucocorticoids in tumor stroma

1995 ◽  
Vol 108 (6) ◽  
pp. 2153-2162 ◽  
Author(s):  
J.F. Talts ◽  
A. Weller ◽  
R. Timpl ◽  
M. Ekblom ◽  
P. Ekblom
Keyword(s):  
Extracellular Matrix ◽  
Growth Factors ◽  
Growth Factor ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tenascin C ◽  
Extracellular Matrix Components ◽  
Growth Factor Beta ◽  
Matrix Components

We have here studied the composition and regulation of stromal extracellular matrix components in an experimental tumor model. Nude mice were inoculated with WCCS-1 cells, a human Wilms' tumor cell line. In the formed tumors the stroma was found to contain mesenchymal extracellular matrix proteins such as tenascin-C, fibulins-1 and 2 and fibronectin, but no nidogen. Nidogen was confined to basement membranes of tumor blood vessels. Since glucocorticoids have been shown to downregulate tenascin-C expression in vitro, we tested whether dexamethasone can influence biosynthesis of extracellular matrix components during tumor formation in vivo. A downregulation of tenascin-C mRNA and an upregulation of fibronectin mRNA expression by dexamethasone was noted. Transforming growth factor-beta 1 mRNA levels were unaffected by the dexamethasone treatment. Glucocorticoids can thus downregulate tenascin-C synthesis although local stimulatory growth factors are present. The competition between a negative and a positive extrinsic factor on synthesis of stromal extracellular matrix components was studied in a fibroblast/preadipocyte cell line. Transforming growth factor-beta 1 stimulated tenascin-C synthesis but did not affect fibronectin or fibulin-2 synthesis. Dexamethasone at high concentrations could completely suppress the effect of transforming growth factor-beta 1 on tenascin-C mRNA expression. Transforming growth factor-beta 1 could in turn overcome the downregulation of tenascin-C mRNA expression caused by a lower concentration of dexamethasone. We therefore suggest that the limited expression of tenascin-C in part is due to a continuous suppression by physiological levels of glucocorticoids, which can be overcome by local stimulatory growth factors when present in sufficient amounts.

Abstract 3030: Differential Regulation of Valvular Interstitial Cell Dysfunction by Extracellular Matrix Components

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Karien J Rodriguez ◽  
Kristyn S Masters
Keyword(s):  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Lower Amount ◽  
Valvular Interstitial Cells ◽  
Cell Dysfunction ◽  
Endogenous Production ◽  
Extracellular Matrix Components ◽  
Culture Surface

Calcification is the leading cause of bioprosthetic and native aortic valve failure, but relatively little is known regarding the factors that contribute to the progression of valvular calcification. Because extracellular matrix (ECM) disarray is often observed in explanted diseased valves, we have investigated the role of individual ECM components in the in vitro calcification of valvular interstitial cells (VICs). The transformation of VICs to an osteoblast-like phenotype was quantified in VICs cultured on different types of ECM coatings. The results show that the number and size of calcific nodules formed in VIC cultures, as well as the expression of mineralization markers alkaline phosphatase (ALP) and CBFa1, were highly dependent upon the composition of the culture surface. In fact, VICs cultured on certain ECM components, namely collagen (Coll) and fibronectin (FN), were resistant to calcification, even upon treatment with potent mineralization-inducing growth factors, such as transforming growth factor beta1 (TGFb1). Meanwhile, VIC cultures on fibrin (FB), laminin, and heparin not only had a high number of calcified nodules (p<0.001 vs. Coll, FN), but also elevated levels of ALP and CBFa1 (p<0.02), and the number of nodules on these ‘pro-calcific’ coatings significantly increased upon treatment with exogenous TGFb1 (p<0.05). To explain the ECM-dependence of calcification, the endogenous production of a pro-mineralization factor (TGFb1) was assessed in VICs on anti-calcific (Coll) and pro-calcific (FB) substrates. Quantification of TGFb1 mRNA revealed that VICs on Coll surfaces expressed a significantly lower amount of TGFb1 mRNA than VICs on FB (p<0.01). Furthermore, treatment with a neutralizing antibody to TGFb1 decreased TGFb1 mRNA expression by VICs on Coll in comparison to VICs on FB or polystyrene controls (p<0.02). Thus, we have discovered a strong correlation between VIC calcification and ECM composition. Our findings show that the ECM plays an important role in controlling TGFb1 expression and subsequent calcification of VICs, which may significantly impact the design of biomaterials for valve tissue engineering, understanding of valvular disease, and the development of preventative treatments for valve calcification.

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