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New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration
Author(s) -
PasteuningVuhman Svitlana,
Boertjevan 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.,
AartsmaRus Annemieke,
Loomans Cindy J. M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600675r
Subject(s) - myostatin , endocrinology , medicine , duchenne muscular dystrophy , skeletal muscle , biology , muscle atrophy , activin receptor , muscle hypertrophy , transforming growth factor
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