New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

Pasteuning-Vuhman, Svitlana; Meulen, J. W. Boertje-van der; Putten, Maaike van; Overzier, Maurice; Dijke, Peter ten; Kiełbasa, Szymon M.; Arindrarto, Wibowo; Wolterbeek, Ron; Lezhnina, Ksenia; Ozerov, Ivan V.; Aliper, Aleksandr M; Hoogaars, Willem M.H.; Aartsma‐Rus, Annemieke; Loomans, Cindy J.M.

doi:10.1096/fj.201600675r

Cited by 27 publications

(22 citation statements)

References 64 publications

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“…Alk1 was upregulated in the gastrocnemius and diaphragm muscle of LGMD mice ( Fig 5c ). Alk4 , which was previously described as a specific myostatin type I receptor in muscles [ 21 , 22 ] was significantly increased in LGMD diaphragm muscle. Similar to Acvr2a and Acvr2b results, SGCD-null males expressed significantly higher Alk4 levels than did females.…”

Section: Resultsmentioning

confidence: 99%

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

et al. 2017

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Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart.Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice.

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Section: Resultsmentioning

confidence: 99%

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

et al. 2017

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“…In previous studies, myostatin has been demonstrated to inhibit the myogenic differentiation of C2C12 cells [54,55]. ACVR1B inhibition promoted myogenetic differentiation in C2C12 in vitro, and reduced muscle mass and muscle fiber size in ACVR1B -silencing mice [18]. It is logical that miR-24-2 promotes differentiation by inhibiting ACVR1B expression to block myostatin signaling.…”

Section: Discussionmentioning

confidence: 99%

“…It is known to participate in embryonic development, nervous system differentiation, germ cell development, tumor formation, and immunosuppression [15,16,17]. ACVR1B influences myogenesis and regulates the balance between protein synthesis and degradation by modulating the MSTN pathway to maintain muscle mass [18]. In addition, miR-210 regulates transforming growth factor-β (TGF-β)/activin signaling to promote osteoblastic differentiation by targeting ACVR1B [19].…”

Section: Introductionmentioning

confidence: 99%

Bta-miR-24-3p Controls the Myogenic Differentiation and Proliferation of Fetal Bovine Skeletal Muscle-Derived Progenitor Cells by Targeting ACVR1B

Xing

Ren

et al. 2019

Animals

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Simple SummaryMicroRNAs play pivotal roles in skeletal muscle development, but the molecular basis of their functions in fetal bovine skeletal muscle development is largely unknown. Here, we report a mechanistic study of bta-miR-24-3p, a key miRNA regulator of the myogenic differentiation of fetal bovine platelet-derived growth factor receptor alpha negative (PDGFRα-) progenitor cells. We isolated progenitor cells from the bovine fetal longissimus dorsi muscle and purified them with PDGFRα antibodies to remove fibro-adipogenic progenitors. We observed elevated bta-miR-24-3p expression during differentiation, and bta-miR-24-3p overexpression led to promoted myogenic differentiation but suppressed proliferation. Moreover, activin receptor type 1B (ACVR1B) was identified as a direct target of bta-miR-24-3p, and ACVR1B-silencing cells exhibited similar phenotypes to bta-miR-24-3p-overexpressing bovine PDGFRα- progenitor cells. These results extended our understanding on the roles of miRNA in fetal muscle development. The method of removing fibro-adipogenic progenitors in our study will also provide useful information for other investigators.AbstractMicroRNAs modulate a variety of cellular events, including skeletal muscle development, but the molecular basis of their functions in fetal bovine skeletal muscle development is poorly understood. In this study, we report that bta-miR-24-3p promotes the myogenic differentiation of fetal bovine PDGFRα- progenitor cells. The expression of bta-miR-24-3p increased during myogenic differentiation. Overexpression of bta-miR-24-3p significantly promoted myogenic differentiation, but inhibited proliferation. A dual-luciferase assay identified ACVR1B as a direct target of bta-miR-24-3p. Similarly, knocking down ACVR1B by RNA interference also significantly inhibited proliferation and promoted the differentiation of bovine PDGFRα- progenitor cells. Thus, our study provides a mechanism in which bta-miR-24-3p regulates myogenesis by inhibiting ACVR1B expression.

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“…Activin-A binds to a set of receptors (ALK4, ALK7, ActRIIA, and ActRIIB) distinct from those used by the TGF-b isoforms (Loomans and Andl, 2016). Activin-A and its receptor dimer comprising ALK4 and ACVR2A/B play a critical role in muscular development (Pasteuning-Vuhman et al, 2017), and can be produced in large amounts by dendritic cells (DCs) or following acute inflammation (Jones et al, 2004;Robson et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

et al. 2019

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Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor–β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)–dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD2/3 to suppress IL-15–mediated NK cell metabolism. Activin-A impaired human and mouse NK cell proliferation and reduced the production of granzyme B to impair tumor killing. Similar to TGF-β, activin-A also induced SMAD2/3 phosphorylation and stimulated NK cells to increase their cell surface expression of several markers of ILC1 cells. Activin-A also induced these changes in TGF-β receptor–deficient NK cells, suggesting that activin-A and TGF-β stimulate independent pathways that drive SMAD2/3-mediated NK cell suppression. Last, inhibition of activin-A by follistatin substantially slowed orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-β–independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.

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New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

Cited by 27 publications

References 64 publications

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

Bta-miR-24-3p Controls the Myogenic Differentiation and Proliferation of Fetal Bovine Skeletal Muscle-Derived Progenitor Cells by Targeting ACVR1B

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

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