Altered bone‐regulating myokine expression in skeletal muscle Of Duchenne muscular dystrophy mouse models

Zhou, Shumin; Qian, Baoli; Wang, Ling; Zhang, Changqing; Hogan, MaCalus V.; Li, Hongshuai

doi:10.1002/mus.26195

Cited by 18 publications

(36 citation statements)

References 74 publications

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“…It has been reported that besides the liver, which is the main FGF‐21 secretory organ, FGF‐21 can also be secreted by adipose tissue and skeletal muscle . We have recently shown that FGF‐21 mRNA and protein expressions are dramatically upregulated in dystrophic skeletal muscles . To further identify the origin of the elevated circulating FGF‐21 in dystrophic mice, we compared the levels of protein and transcript abundance of FGF‐21 in liver, WAT, and skeletal muscles (TA and diaphragm) in WT and dystrophic mice.…”

Section: Resultsmentioning

confidence: 99%

“…Primer sequences used in this study are listed in Supplementary Table 1. Eukaryotic translation elongation factor 2 (eEF2) was used as an endogenous invariant control for data normalization . Target gene expression, normalized to eEF2, was determined using ∆∆Ct mathematical model normalized to the expression in controls.…”

Section: Methodsmentioning

confidence: 99%

“…Lumbar spine, femur, tibia, and skull were collected at euthanasia and fixed in 4% paraformaldehyde for 24 hours. μCT scans were performed to evaluate bone volume (BV) and architectures of lumbar vertebrae, mid‐shaft of femur, proximal tibia (metaphyseal and epiphyseal parts), and skull (parietal bone) using Viva‐CT 40 (SCANCO Medical AG, Brüttisellen, Switzerland) with the following settings: energy 70 kV, intensity 114 μA, integration time 300 ms, and isotropic voxel size of 10.5 μm as described . Regions of interest included the trabecular bones from lumbar vertebrae, metaphyseal/epiphyseal parts of proximal tibia, and cortical bones from mid‐shaft of femur.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we have reported that dystrophic dKO mice exhibit a spectrum of degenerative changes in bone (bone loss in both long bones and vertebra), articular cartilage, and intervertebral discs, which closely represent the degenerative skeletal phenotypes observed in DMD patients . Recently, we reported, for the first time, that the expression of FGF‐21 was increased dramatically in dystrophic skeletal muscles compared to those in WT controls . FGF‐21 is an atypical member of the FGF family that lacks a heparin domain; it also functions as a powerful endocrine and paracrine regulator of glucose and lipid metabolism during prolonged fasting .…”

Section: Introductionmentioning

confidence: 94%

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Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Sun

Qian

et al. 2019

Journal of Bone and Mineral Research

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Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy seen in children. In addition to skeletal muscle, DMD also has a significant impact on bone. The pathogenesis of bone abnormalities in DMD is still unknown. Recently, we have identified a novel bone‐regulating cytokine, fibroblast growth factor‐21 (FGF‐21), which is dramatically upregulated in skeletal muscles from DMD animal models. We hypothesize that muscle‐derived FGF‐21 negatively affects bone homeostasis in DMD. Dystrophin/utrophin double‐knockout (dKO) mice were used in this study. We found that the levels of circulating FGF‐21 were significantly higher in dKO mice than in age‐matched WT controls. Further tests on FGF‐21 expressing tissues revealed that both FGF‐21 mRNA and protein expression were dramatically upregulated in dystrophic skeletal muscles, whereas FGF‐21 mRNA expression was downregulated in liver and white adipose tissue (WAT) compared to WT controls. Neutralization of circulating FGF‐21 by i.p. injection of anti‐FGF‐21 antibody significantly alleviated progressive bone loss in weight‐bearing (vertebra, femur, and tibia) and non–weight bearing bones (parietal bones) in dKO mice. We also found that FGF‐21 directly promoted RANKL‐induced osteoclastogenesis from bone marrow macrophages (BMMs), as well as promoted adipogenesis while concomitantly inhibiting osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). Furthermore, fibroblast growth factor receptors (FGFRs) and co‐receptor β‐klotho (KLB) were expressed in bone cells (BMM‐derived osteoclasts and BMMSCs) and bone tissues. KLB knockdown by small interfering RNAs (siRNAs) significantly inhibited the effects of FGF21 on osteoclast formation of BMMs and on adipogenic differentiation of BMMSCs, indicating that FGF‐21 may directly affect dystrophic bone via the FGFRs‐β‐klotho complex. In conclusion, this study shows that dystrophic skeletal muscles express and secrete significant levels of FGF‐21, which negatively regulates bone homeostasis and represents an important pathological factor for the development of bone abnormalities in DMD. The current study highlights the importance of muscle/bone cross‐talk via muscle‐derived factors (myokines) in the pathogenesis of bone abnormalities in DMD. © 2019 American Society for Bone and Mineral Research.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Sun

Qian

et al. 2019

Journal of Bone and Mineral Research

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“…S2). However, inflammatory factors released from dystrophic muscle that have been reported to stimulate osteoclastogenesis such as IL‐6 , IL‐1β , and Fgf21 were all inhibited by growth hormone treatment. Further investigation is needed to determine if the suppression of mRNA encoding these three factors and possibly others contributes to changes in bone resorption by growth hormone.…”

Section: Discussionmentioning

confidence: 97%

Growth Hormone Increases Bone Toughness and Decreases Muscle Inflammation in Glucocorticoid-Treated Mdx Mice, Model of Duchenne Muscular Dystrophy

Yoon

Grynpas

Mitchell

2019

Journal of Bone and Mineral Research

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The absence of functional dystrophin with mutations of the dystrophin‐encoding gene in Duchenne muscular dystrophy (DMD) results in muscle inflammation and degeneration, as well as bone fragility. Long‐term glucocorticoid therapy delays the muscular disease progression but suppresses growth hormone secretion, resulting in short stature and further deleterious effects on bone strength. This study evaluated the therapeutic potential of daily growth hormone therapy in growing mdx mice as a model of DMD. Growth hormone treatment on its own or in combination with glucocorticoids significantly improved muscle histology and function and decreased markers of inflammation in mdx mice. Glucocorticoid treatment thinned cortical bone and decreased bone strength and toughness. Despite the minimal effects of growth hormone on bone microarchitecture, it significantly improved biomechanical properties of femurs and vertebrae, even in the presence of glucocorticoid treatment. Together these studies suggest that the use of growth hormone in DMD should be considered for improvements to muscle and bone health. © 2019 American Society for Bone and Mineral Research.

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Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

Starosta

Konieczny

2021

Cell. Mol. Life Sci.

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Duchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.

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Altered bone‐regulating myokine expression in skeletal muscle Of Duchenne muscular dystrophy mouse models

Cited by 18 publications

References 74 publications

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Growth Hormone Increases Bone Toughness and Decreases Muscle Inflammation in Glucocorticoid-Treated Mdx Mice, Model of Duchenne Muscular Dystrophy

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

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