New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration
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 oligon...
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| creator | Pasteuning‐Vuhman, Svitlana Boertje‐van der Meulen, Johanna W. Putten, Maaike Van Overzier, Maurice Dijke, Peter Kielbasa, Szymon M. Arindrarto, Wibowo Wolterbeek, Ron Lezhnina, Ksenia V. Ozerov, Ivan V. Aliper, Aleksandr M. Hoogaars, Willem M. Aartsma‐Rus, Annemieke Loomans, Cindy J. M. |
| description | 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 my oblast differentiation in vitro. Unexpectedly, amarked 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, musclemass decreased evenmore. RNA seq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases my ogenesis 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 derMeulen, J. W., Van Putten, M., Overzier, M., ten Dijke, P., Kielbasa, 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. FASEB J. 31, 238–255 (2017) www.fasebj.org |
| doi_str_mv | 10.1096/fj.201600675r |
| format | Article |
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M.</creator><creatorcontrib>Pasteuning‐Vuhman, Svitlana ; Boertje‐van der Meulen, Johanna W. ; Putten, Maaike Van ; Overzier, Maurice ; Dijke, Peter ; Kielbasa, Szymon M. ; Arindrarto, Wibowo ; Wolterbeek, Ron ; Lezhnina, Ksenia V. ; Ozerov, Ivan V. ; Aliper, Aleksandr M. ; Hoogaars, Willem M. ; Aartsma‐Rus, Annemieke ; Loomans, Cindy J. M.</creatorcontrib><description>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 my oblast differentiation in vitro. Unexpectedly, amarked 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, musclemass decreased evenmore. RNA seq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases my ogenesis 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 derMeulen, J. W., Van Putten, M., Overzier, M., ten Dijke, P., Kielbasa, 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. 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M.</creatorcontrib><title>New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>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 my oblast differentiation in vitro. Unexpectedly, amarked 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, musclemass decreased evenmore. RNA seq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases my ogenesis 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 derMeulen, J. W., Van Putten, M., Overzier, M., ten Dijke, P., Kielbasa, 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. FASEB J. 31, 238–255 (2017) www.fasebj.org</description><subject>Activin</subject><subject>Activin Receptors, Type I - genetics</subject><subject>Activin Receptors, Type I - metabolism</subject><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>Atrophy</subject><subject>Base Sequence</subject><subject>Cell Line</subject><subject>DNA Damage</subject><subject>Down-Regulation</subject><subject>Duchenne muscular dystrophy</subject><subject>Duchenne's muscular dystrophy</subject><subject>Dystrophy</subject><subject>Exon skipping</subject><subject>Fibrosis</subject><subject>Gene Expression Regulation - physiology</subject><subject>Inhibition</subject><subject>Mice</subject><subject>Mice, Inbred mdx</subject><subject>Muscle Development - physiology</subject><subject>muscle mass</subject><subject>muscle metabolism</subject><subject>Muscle, Skeletal - physiology</subject><subject>Muscles</subject><subject>Muscular dystrophy</subject><subject>Musculoskeletal system</subject><subject>Myoblasts - physiology</subject><subject>Myogenesis</subject><subject>Myostatin</subject><subject>myostatin/activin pathway</subject><subject>Oligonucleotides</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Protein biosynthesis</subject><subject>Protein synthesis</subject><subject>Regeneration</subject><subject>Regeneration - genetics</subject><subject>Regeneration - physiology</subject><subject>RNA - genetics</subject><subject>RNA - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Skeletal muscle</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqNkc1vFCEYxonR2LV69GpIvNTDtHwMDMTEpDauVjeaVD0TloHubGZgBKbN_Pey2Xb9OBhPb_K8Px4eeAB4jtEpRpKfue0pQZgjxBsWH4AFZhRVXHD0ECyQkKTinIoj8CSlLUIIF_QxOCJNQ2nN0ALkz_YWusmb3AUPg4N5Y-Ewh5R17vyZLvpN52GeRwsvYbTGjjlEeHK--lS_gjpBDQfbdnonltPDlExvoc4xjJsZat_eS9FeW2-j3t3zFDxyuk_22d08Bt-X775dfKhWX95fXpyvKsMxuqocbp1uHXEtqp3AlCGzbteN1Exo3RLUSCOI01SuW946iUntEDEEc-F0g6Smx-DN3nec1iWlsT5H3asxdoOOswq6U39ufLdR1-FGMcwxw3UxOLkziOHHZFNWQ5eM7XvtbZiSwoLJWsia0_9AKasRY5QV9OVf6DZM0ZefUFiKmjZcclKoak-ZGFKK1h1yY6R21Su3Vb-qL_yL3x97oO-7LsDrPXDb9Xb-t5tafn1Llh8PwhX9CVUNvIU</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Pasteuning‐Vuhman, Svitlana</creator><creator>Boertje‐van der Meulen, Johanna W.</creator><creator>Putten, Maaike Van</creator><creator>Overzier, Maurice</creator><creator>Dijke, Peter</creator><creator>Kielbasa, Szymon M.</creator><creator>Arindrarto, Wibowo</creator><creator>Wolterbeek, Ron</creator><creator>Lezhnina, Ksenia V.</creator><creator>Ozerov, Ivan V.</creator><creator>Aliper, Aleksandr M.</creator><creator>Hoogaars, Willem M.</creator><creator>Aartsma‐Rus, Annemieke</creator><creator>Loomans, Cindy J. 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M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2017-01</date><risdate>2017</risdate><volume>31</volume><issue>1</issue><spage>238</spage><epage>255</epage><pages>238-255</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><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 my oblast differentiation in vitro. Unexpectedly, amarked 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, musclemass decreased evenmore. RNA seq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases my ogenesis 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 derMeulen, J. W., Van Putten, M., Overzier, M., ten Dijke, P., Kielbasa, 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. FASEB J. 31, 238–255 (2017) www.fasebj.org</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>27733450</pmid><doi>10.1096/fj.201600675r</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Activin Activin Receptors, Type I - genetics Activin Receptors, Type I - metabolism Animals Antisense oligonucleotides Atrophy Base Sequence Cell Line DNA Damage Down-Regulation Duchenne muscular dystrophy Duchenne's muscular dystrophy Dystrophy Exon skipping Fibrosis Gene Expression Regulation - physiology Inhibition Mice Mice, Inbred mdx Muscle Development - physiology muscle mass muscle metabolism Muscle, Skeletal - physiology Muscles Muscular dystrophy Musculoskeletal system Myoblasts - physiology Myogenesis Myostatin myostatin/activin pathway Oligonucleotides Oligonucleotides, Antisense - pharmacology Protein biosynthesis Protein synthesis Regeneration Regeneration - genetics Regeneration - physiology RNA - genetics RNA - metabolism Rodents Signal Transduction Skeletal muscle |
| title | New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration |
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