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

Abstract

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...

The functional role of hemojuvelin in acute ischemic stroke

“…52 The direct interaction between HJV and TGF-b on skeletal muscle was observed in recently published muscle-wasting models by muscle-specific HJV knockout mice, and HJV is a suppressor to inhibit TGF-bs signaling in cell membrane. 53 Correspondingly, our result using HJV knockout mice and siHJV neuron has identified the negative correlation between HJV and TGF-b in vivo and in vitro ( Supplementary Figure 6). The basal levels of TGF-b in siHJV mice neuron and HJV knockout mice are not merely higher than control groups, and the elevations of TGF-b are also far above than control groups which receive OGD or stroke treatment.…”

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

“…In the context of skeletal muscle, inhibition of TGF-β1 has been linked to improvement in muscle regeneration and decreased fibrosis (Davies et al, 2016; Song et al, 2017; Zhang et al, 2019), consistent with the importance of the TGF-β1 signaling in regulating both regeneration and matrix production. Several works have elucidated the detrimental, cell-autonomous, impact of TGF-β signaling on muscle stem cells by inhibiting their activation (Carlson et al, 2008; Wang et al, 2016) and terminal differentiation (Carlson et al, 2008) while promoting a fibrogenic switch in chronically degenerating muscles (Biressi et al, 2014).…”

Transforming Growth Factor-Beta in Skeletal Muscle Wasting

“…Does the presence of TGF-β from bone induce muscle to express more TGF-β? A more recent paper by Zhang et al [22] that identified an intrinsic TGF-β inhibitor in liver, hemojuvelin, which could suppress TGF-β in muscle from both Duchenne muscular dystrophy and from aging mice, is also consistent with increased muscle TGF-β production in aging animals.…”