Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

Chen, Justin; Walton, Kelly L.; Hagg, Adam; Colgan, Timothy D.; Johnson, Katharine E.; Qian, Hongwei; Gregorevic, Paul; Harrison, Craig A.

doi:10.1073/pnas.1620013114

Cited by 97 publications

(122 citation statements)

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“…For example, the inhibition of TGF‐β1 signalling by losartan treatment had dramatically beneficial effects on sarcopenic muscle by improving the regeneration after injury . Inhibition of TGF‐β1 ligands in mouse models of muscular dystrophy has been shown to variously reduce muscle fibrosis and increase mass and strength . However, TGF‐β1 signalling is found ubiquitously throughout the body, and disruption of this pathway is thus associated with several disease conditions, such as pathological cardiac diseases, bone, and connective tissue disorders .…”

Section: Discussionmentioning

confidence: 99%

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Zhang

Wang

et al. 2019

J cachexia sarcopenia muscle

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Background Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor‐β1 (TGF‐β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF‐β1 signalling is a promising therapeutic strategy for muscle‐wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane‐bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF‐β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF‐β1 signalling. Methods Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT‐PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro . Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual‐luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF‐β1 signalling in skeletal muscle. Results Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down‐regulated in the muscles of DMD patients ( n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans ( n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age‐related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p‐Smad1/5/8 signalling pathway was unchanged, but TGF‐β1, TGF‐β receptor II (TβRII), and p‐Smad2/3 expression were increased in Hjv‐ deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF‐β1, whereas Hjv overexpression inhibited TGF‐β1/Smad3 signalling by directly interacting with TβRII on the muscle membrane. Conclusions Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF‐β1/Smad3 signalling as a coreceptor for TβRII. Unlike the TGF‐β1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age‐re...

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Section: Discussionmentioning

confidence: 99%

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Zhang

Wang

et al. 2019

J cachexia sarcopenia muscle

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“…In addition to Mstn, Activins, additional members in TGF-β/Activin signaling branch, have also been shown to negatively affect the muscle mass (Chen, et al, 2017;Chen, et al, 2014). The Mstn and Activins appear to synergize in suppressing muscle growth since co-inhibition of both factors resulted in a greater increases in muscle mass than those in which the activity of individual factors was inhibited (Chen, et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…This is analogous to what happens during muscle disuse (Gustafsson, et al, 2010;Reardon, et al, 2001;Wehling, et al, 2000) and cancer cachexia (Loumaye, et al, 2015;Marino, et al, 2015;Lokireddy, et al, 2012), in which muscle wasting correlates with the increased expression of Mstn or Activins. Interestingly, cancer cachexia was reversed by prodomain-derived ligand-specific antagonists (Chen, et al, 2017) or by a decoy receptor of ActRIIB (Zhou, et al, 2010). Besides reversing the cancer cachexia, inhibition of Mstn or Activins is also known to alleviate the atrophy and malfunctioning of dystrophic muscle (Chen, et al, 2017;Bogdanovich, et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, cancer cachexia was reversed by prodomain-derived ligand-specific antagonists (Chen, et al, 2017) or by a decoy receptor of ActRIIB (Zhou, et al, 2010). Besides reversing the cancer cachexia, inhibition of Mstn or Activins is also known to alleviate the atrophy and malfunctioning of dystrophic muscle (Chen, et al, 2017;Bogdanovich, et al, 2002). Therefore, Mstn-and Activin-induced signaling pathways appear to play essential roles in the development of pathogenic muscle wasting associated with cancer, dystrophy, and perhaps age related sarcopenia (Bergen, et al, 2015;White and LeBrasseur, 2014) and may provide potent therapeutic targets for the treatment of muscle atrophy in multiple settings.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, overexpression of mstn via in vivo transfection in the adult muscle leads to attenuated phosphorylation of AKT, S6 and 4E-BP (Amirouche, et al, 2009). Conversely, inhibition of Mstn and Activin by prodomain-derived antagonists leads to increased phosphorylation of mTOR and S6RP (Chen, et al, 2017). In addition, administration of a soluble decoy receptor of ActRIIB to adult mice resulted in increased phosphorylation of AKT and FOXO3a in skeletal muscle (Zhou, et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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DrosophilaActivin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes

Kim

O’Connor

2020

Preprint

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The Myostatin/Activin branch of the TGF superfamily acts as a negative regulator of mammalian skeletal muscle size, in part, through downregulation of insulin/IGF-1 signaling.Surprisingly, recent studies in Drosophila indicate that Activin signaling acts as a positive regulator of muscle size. In this study, we demonstrate that Drosophila Activin signaling positively regulates the InR/dTORC1 pathway and the level of MHC, an essential sarcomeric protein, via promoting the transcription of Pdk1 and Akt1. Enhancing InR/dTORC1 signaling in the muscle of Activin pathway mutants restores MHC levels close to wild-type, but only increased the width of muscle cells. In contrast, hyperactivation of the Activin pathway increases the length of muscle cells even when MHC levels were lowered by suppression of dTORC1.Together, these results indicate that Drosophila Activin pathway regulates larval muscle geometry via promoting InR/dTORC1-dependent MHC production and the differential assembly of sarcomeric components into either pre-existing (width) or new (length) sarcomeric units depending on the balance of InR/dTORC1 and Activin signals.

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Emerging role of TAK1 in the regulation of skeletal muscle mass

2023

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Maintenance of skeletal muscle mass and strength throughout life is crucial for heathy living and longevity. Several signaling pathways have been implicated in the regulation of skeletal muscle mass in adults. TGF-β-activated kinase 1 (TAK1) is a key protein, which coordinates the activation of multiple signaling pathways. Recently, it was discovered that TAK1 is essential for the maintenance of skeletal muscle mass and myofiber hypertrophy following mechanical overload. Forced activation of TAK1 in skeletal muscle causes hypertrophy and attenuates denervation-induced muscle atrophy. TAK1-mediated signaling in skeletal muscle promotes protein synthesis, redox homeostasis, mitochondrial health, and integrity of neuromuscular junctions. In this article, we have reviewed the role and potential mechanisms through which TAK1 regulates skeletal muscle mass and growth. We have also proposed future areas of research that could be instrumental in exploring TAK1 as therapeutic target for improving muscle mass in various catabolic conditions and diseases.

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Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

Cited by 97 publications

References 50 publications

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

DrosophilaActivin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes

Emerging role of TAK1 in the regulation of skeletal muscle mass

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