Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration

Pascoe, Amy; Johnston, Amelia J.; Murphy, Robyn M.

doi:10.1007/s00018-020-03495-x

Cited by 24 publications

(34 citation statements)

References 67 publications

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“…Nevertheless, administration of Fc-Tweak did improve muscle pathology in SMA mice as demonstrated by the partial restoration of molecular markers of muscle health and myofiber size. These results support a role for the TWEAK/Fn14 pathway in maintaining skeletal muscle health and homeostasis [21]. However, it is important to note that the TWEAK/Fn14 pathway is involved in many other tissues and pathologies such as tumor development and metastasis, heart-related diseases [90], kidney injury, cerebral ischemia [91, 92] and autoimmune diseases [93, 94], which could have influenced the overall impact of systemically administered Fc-Tweak on muscle health and disease progression in SMA mice.…”

Section: Discussionsupporting

confidence: 66%

“…In summary, our results demonstrate a potential role and contribution of the TWEAK/Fn14 pathway to myopathy and glucose metabolism perturbations in SMA muscle. Furthermore, our study, combined with previous work in adult models [20, 21], suggests that dysregulation of the TWEAK/Fn14 signaling in muscle appears to be dependent on the origin of the muscle pathology (e.g. denervation vs intrinsic) and developmental stage of skeletal muscle (e.g.…”

Section: Discussionsupporting

confidence: 66%

“…We observed that mRNA levels of NIK were significantly increased in TA muscle of P7 Smn -/- ; SMN2 mice compared to WT animals (Fig. 1j), suggesting that dysregulated activity of the Tweak/Fn14 in skeletal muscle of SMA mice impacts both the canonical and non-canonical NF-κB pathways, which play key regulatory roles in muscle health and metabolism [20, 21].…”

Section: Resultsmentioning

confidence: 99%

“…chronic vs acute) and primary origin of muscle pathology (e.g. denervation vs intrinsic insult) [20, 21].…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

Meijboom

McFall

Anthony

et al. 2021

Preprint

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Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

“…chronic vs acute) and primary origin of muscle pathology (e.g. denervation vs intrinsic insult) [20, 21].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

Meijboom

McFall

Anthony

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The main downstream pathways activated by the TWEAK-Fn14 signaling axis are NF-кB, MAPK, and PI3K/Akt signaling. It is worth noting that the signal pathway activation may depend on the dose, target tissue, and duration of action(Pascoe et al, 2020).4.1 | In vitro studies of targeted therapy hTWEAK upregulated the expression of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 in human proximal tubular cells, and downregulated the expression of E-cadherin. These effects can be reversed by anti-TWEAK mAb (Z. Liu et al, 2016).…”

mentioning

confidence: 99%

TWEAK/Fn14 axis is an important player in fibrosis

Zhang

Zeng

Xia

2020

Journal Cellular Physiology

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Fibrosis is a common pathological condition associated with abnormal repair after tissue injury. However, the etiology and molecular mechanisms of fibrosis are still not well‐understood. Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK) belongs to the TNF superfamily and acts by binding to its receptor, fibroblast growth factor‐inducible 14 (Fn14), thereby activating a variety of intracellular signal transduction pathways in various types of cells. Besides promoting the expression of growth factors, activation of TWEAK/Fn14 signaling after tissue injury can promote the expression of pro‐inflammatory cytokines, which trigger the immune response, thereby exacerbating the injury. Severe or repetitive injury leads to a dysregulated tissue repair process, in which the TWEAK/Fn14 axis promotes the activation and proliferation of myofibroblasts, induces the secretion of the extracellular matrix, and regulates profibrotic mediators to further perpetuate and sustain the fibrotic process. In this review, we summarize the available experimental evidence on the underlying molecular mechanisms by which the TWEAK/Fn14 pathway mediates the development and progression of fibrosis. In addition, we discuss the therapeutic potential of the TWEAK/Fn14 pathway in fibrosis‐associated diseases based on evidence derived from multiple models and cells from injured tissue and fibrotic tissue.

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Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1

Song

et al. 2023

J cachexia sarcopenia muscle

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Background Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1. Methods In vivo studies were carried out in impaired leg muscles from patients with lumbar disc herniation, two mouse models for skeletal muscle atrophy (denervation and cancer cachexia) and heterozygous Aggf1+/− mice. Mouse muscle atrophy phenotypes were characterized by body weight and myotube cross‐sectional areas (CSA) using H&E staining and immunostaining for dystrophin. Molecular mechanistic studies include co‐immunoprecipitation (Co‐IP), western blotting, quantitative real‐time PCR analysis and immunostaining analysis. Results Heterozygous Aggf1+/− mice showed exacerbated phenotypes of reduced muscle mass, myotube CSA, MyHC (myosin heavy chain) and α‐actin, increased inflammation (macrophage infiltration), apoptosis and fibrosis after denervation and cachexia. Intramuscular and intraperitoneal injection of recombinant AGGF1 protein attenuates atrophy phenotypes in mice with denervation (gastrocnemius weight 81.3 ± 5.7 mg vs. 67.3 ± 5.1 mg for AGGF1 vs. buffer; P < 0.05) and cachexia (133.7 ± 4.7 vs. 124.3 ± 3.2; P < 0.05). AGGF1 expression undergoes remodelling and is up‐regulated in gastrocnemius and soleus muscles from atrophy mice and impaired leg muscles from patients with lumbar disc herniation by 50–60% (P < 0.01). Mechanistically, AGGF1 interacts with TWEAK (tumour necrosis factor‐like weak inducer of apoptosis), which reduces interaction between TWEAK and its receptor Fn14 (fibroblast growth factor‐inducing protein 14). This leads to inhibition of Fn14‐induced NF‐kappa B (NF‐κB) p65 phosphorylation, which reduces expression of muscle‐specific E3 ubiquitin ligase MuRF1 (muscle RING finger 1), resulting in increased MyHC and α‐actin and partial reversal of atrophy phenotypes. Autophagy is reduced in Aggf1+/− mice due to inhibition of JNK (c‐Jun N‐terminal kinase) activation in denervated and cachectic muscles, and AGGF1 treatment enhances autophagy in two atrophy models by activating JNK. In impaired leg muscles of patients with lumbar disc herniation, MuRF1 is up‐regulated and MyHC and α‐actin are down‐regulated; these effects are reversed by AGGF1 by 50% (P < 0.01). Conclusions These results indicate that AGGF1 is a novel regulator for the pathogenesis of skeletal muscle atrophy and attenuates skeletal muscle atrophy by promoting autophagy and inhibiting MuRF1 expression through a molecular signalling pathway of AGGF1‐TWEAK/Fn14‐NF‐κB. More importantly, the results indicate that AGGF1 protein therapy may be a novel approach to treat patients with skeletal muscle atrophy.

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Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration

Cited by 24 publications

References 67 publications

Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

TWEAK/Fn14 axis is an important player in fibrosis

Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1

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