Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-β

Rebolledo, Daniela L.; Gonzalez, David J.; Faundez-Contreras, Jennifer; Contreras, Osvaldo; Vio, Carlos P.; Murphy-Ullrich, Joanne E.; Lipson, Kenneth E.; Brandan, Enrique

doi:10.1016/j.matbio.2019.01.002

Cited by 58 publications

(71 citation statements)

References 88 publications

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“…In fact, beyond their supportive role in muscle regeneration, FAPs have been identified as the major source of infiltrating fibroblasts and adipocytes in degenerating dystrophic muscles (Uezumi et al, 2010, 2011; Mozzetta et al, 2013; Kopinke et al, 2017). Similarly, in chronic atrophic conditions, caused by moto-neurons deficits, increased fibrosis is associated with accumulation of FAPs in the interstitium of denervated muscles (Contreras et al, 2016; Fry et al, 2017a; Madaro et al, 2018; Rebolledo et al, 2019). Likewise, intra-muscular fatty infiltration and obesity-associated muscle dysfunctions have been also linked to FAPs accumulation and fibro–adipogenic differentiation (Dammone et al, 2018; Gorski et al, 2018; Kang et al, 2018; Pagano et al, 2018; Buras et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Fibro–Adipogenic Progenitors Cross-Talk in Skeletal Muscle: The Social Network

et al. 2019

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Skeletal muscle is composed of a large and heterogeneous assortment of cell populations that interact with each other to maintain muscle homeostasis and orchestrate regeneration. Although satellite cells (SCs) – which are muscle stem cells – are the protagonists of functional muscle repair following damage, several other cells such as inflammatory, vascular, and mesenchymal cells coordinate muscle regeneration in a finely tuned process. Fibro–adipogenic progenitors (FAPs) are a muscle interstitial mesenchymal cell population, which supports SCs differentiation during tissue regeneration. During the first days following muscle injury FAPs undergo massive expansion, which is followed by their macrophage-mediated clearance and the re-establishment of their steady-state pool. It is during this critical time window that FAPs, together with the other cellular components of the muscle stem cell niche, establish a dynamic network of interactions that culminate in muscle repair. A number of different molecules have been recently identified as important mediators of this cross-talk, and its alteration has been associated with different muscle pathologies. In this review, we will focus on the soluble factors that regulate FAPs activity, highlighting their roles in orchestrating the inter-cellular interactions between FAPs and the other cell populations that participate in muscle regeneration.

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Section: Introductionmentioning

confidence: 99%

Fibro–Adipogenic Progenitors Cross-Talk in Skeletal Muscle: The Social Network

et al. 2019

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“…Similar to previous data showing that CCN2-deficient dermal fibroblasts retained TGFbeta-responsiveness [18], overexpressing CCN3 in human dermal fibroblasts had no appreciable effect on the ability of TGFbeta to induce mRNA expression of endothelin-1 or integrin alpha 11. It should be reiterated that loss or blockade of CCN2 expression severely impairs fibrogenesis including myofibroblast differentiation in vivo in a fashion that does not appear to involve canonical TGFbeta signaling [15, 18–21, 51,52]. Since CCN proteins have limited ex vivo effects and instead act to integrate signaling emanating from multiple sources [30], direct testing of the potential antifibrotic role of CCN3 requires the use of animal models and is therefore beyond the scope of our current report.…”

Section: Discussionmentioning

confidence: 99%

Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts

2019

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The role of the microenvironment in driving connective tissue disease is being increasingly appreciated. Matricellular proteins of the CCN family are signaling modifiers that are secreted by cells into the extracellular matrix microenvironment where they have profound, context-dependent effects on organ development, homeostasis and disease. Indeed, CCN proteins are emergent targets for therapeutic intervention. Recent evidence suggests that, in vivo, CCN3 has effects opposing CCN2. Moreover, when CCN3 expression is high, CCN2 expression is low. That is, they appear to be regulated in a yin/yang fashion, leading to the hypothesis that the CCN2:CCN3 ratio is important to control tissue homeostasis. To begin to test the hypothesis that alterations in CCN2:CCN3 expression might be important in skin biology in vivo, we evaluated the relative ex vivo effects of the profibrotic protein TGFbeta1 on dermal fibroblasts on protein and RNA expression of CCN3 and CCN2, as well as the related protein CCN1. We also used signal transduction inhibitors to begin to identify the signal transduction pathways controlling the ability of fibroblasts to respond to TGFbeta1. As anticipated, CCN1 and CCN2 protein and mRNA were induced by TGFbeta1 in human dermal fibroblasts. This induction was blocked by TAK1, FAK, YAP1 and MEK inhibition. Conversely, TGFbeta1 suppressed CCN3 mRNA expression in a fashion insensitive to FAK, MEK, TAK1 or YAP1 inhibition. Unexpectedly, CCN3 protein was not detected in human dermal fibroblasts basally. These data suggest that, in dermal fibroblasts, the profibrotic protein TGFbeta1 has a divergent effect on CCN3 relative to CCN2 and CCN1, both at the mRNA and protein level. Given that the major source in skin in vivo of CCN proteins are fibroblasts, our data are consistent that alterations in CCN2/CCN1: CCN3 ratios in response to profibrotic agents such as TGFbeta1 may play a role in connective tissue pathologies including fibrosis.

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“…30,31 In the present study, expressions of all mRNA were up-regulated from 3 to 7 d after denervation and maintained to 9 d. Increases in TGF-β1, α-SMA, COL-1α2, and COL-3α1 mRNA in denervated muscle were reported in some studies of gastrocnemius, soleus, and sternocleidomastoid muscles in rodents. [19][20][21][22]32 Palumbo-Zerr et al 33 demonstrated that TGF-β1 induced up-regulation of collagen types 1α1 and 1α2 (encoding types of collagen), which promote fibrosis in human and mouse skin, but the relationship between TGF-β1 and collagen type 1α2 in muscle remains unclear.…”

Section: Effects Of Denervationmentioning

confidence: 99%

“…endomysium, perimysium, and epimysium 16,17 and TGF-β1 have been detected in denervated muscle. 9,[18][19][20][21][22] In addition, connective tissue growth factor, a profibrotic cytokine, is up-regulated by TGF-β1 and induces expression of ECM molecules, such as collagen type 1α2 (COL-1α2). [23][24][25] Hypoxia-inducible factor (HIF)-1α, one of the major proteins expressed under hypoxic state, is increased with physical exercise, 26 hypoxia, 27 and stretching 28…”

Section: Introductionmentioning

confidence: 99%

Fast repetitive stretch suppresses denervation‐induced muscle fibrosis

et al. 2020

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Background: We aimed to examine the influence of different speeds of stretching on denervation-induced skeletal muscle fibrosis. Methods: Stretching was passively applied to rat plantaris muscle denervated by sciatic nerve excision in three different cycles of 0.5, 3, or 12 cycles/min, for 20 min/d for 2 weeks. Results: Gene analysis results showed greater expression of fibrosis-related factors with fast stretching compared with non-stretched muscle. Laser Doppler blood flow analysis indicated reduced intramuscular blood flow during stretching. Histological analysis demonstrated fibrotic area decreases in 12 cycles/min stretched muscle compared with non-stretched muscle. Conclusions: Slower stretching induced greater mRNA expression of collagen and fibroblasts and greater decrement of blood flow. Histologically, faster stretching suppressed fibrosis. These results suggest that fast repetitive stretching of denervated muscle might suppress processes of muscle fibrosis.

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Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-β

Cited by 58 publications

References 88 publications

Fibro–Adipogenic Progenitors Cross-Talk in Skeletal Muscle: The Social Network

Fibro–Adipogenic Progenitors Cross-Talk in Skeletal Muscle: The Social Network

Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts

Fast repetitive stretch suppresses denervation‐induced muscle fibrosis

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