title: New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration.
abstract: Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice. In line with in vitro results, muscle regeneration was stimulated, and muscle fiber size decreased markedly. Notably, when Alk4 was down-regulated in adult wild-type mice, muscle mass decreased even more. RNAseq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases myogenesis but also regulates the tight balance of protein synthesis and degradation. Therefore, caution must be used when developing therapies that interfere with MSTN/activin pathways.-Pasteuning-Vuhman, S., Boertje-van der Meulen, J. W., van Putten, M., Overzier, M., ten Dijke, P., Kiełbasa, S. M., Arindrarto, W., Wolterbeek, R., Lezhnina, K. V., Ozerov, I. V., Aliper, A. M., Hoogaars, W. M., Aartsma-Rus, A., Loomans, C. J. M. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Pasteuning-Vuhman
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Boertje-van der Meulen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van Putten
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maurice
authors.initials: M
authors.lastname: Overzier
authors.affiliation: Department of Molecular and Cell Biology Leiden University Medical Center, Leiden, The Netherlands.|Cancer Genomics Center, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kiełbasa
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wibowo
authors.initials: W
authors.lastname: Arindrarto
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.affiliation: InSilico Medicine, Incorporated, Emerging Technology Centers, Johns Hopkins University, Baltimore, Maryland, USA; and.
authors.forename: Ksenia V
authors.initials: KV
authors.lastname: Lezhnina
authors.affiliation: InSilico Medicine, Incorporated, Emerging Technology Centers, Johns Hopkins University, Baltimore, Maryland, USA; and.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Ozerov
authors.affiliation: InSilico Medicine, Incorporated, Emerging Technology Centers, Johns Hopkins University, Baltimore, Maryland, USA; and.
authors.forename: Aleksandr M
authors.initials: AM
authors.lastname: Aliper
authors.affiliation: Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Move Research Institute Amsterdam, Vrije Universiteit (VU) Amsterdam, Amsterdam, The Netherlands.
authors.forename: Willem M
authors.initials: WM
authors.lastname: Hoogaars
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; a.m.rus@lumc.nl.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cindy J M
authors.initials: CJ
authors.lastname: Loomans
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004249:DNA Damage; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018101:Mice, Inbred mdx; D024510:Muscle Development / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology*; D032446:Myoblasts / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D016376:Oligonucleotides, Antisense; D012313:RNA; D030201:Activin Receptors, Type I; C498933:Acvr1b protein, mouse
keywords: Duchenne muscular dystrophy; antisense oligonucleotides; muscle mass; muscle metabolism; myostatin/activin pathway