Authors
Svitlana Pasteuning-Vuhman, Johanna Boertje-van der Meulen, Maaike van Putten, Maurice Overzier, Peter ten Dijke, Szymon M. Kiełbasa, Wibowo Arindrarto, Ron Wolterbeek, Ksenia V. Lezhnina, Ivan V. Ozerov, Aleksandr M. Aliper, Willem M. Hoogaars, Annemieke Aartsma-Rus & Cindy J. M. Loomans
Journal
The FASEB Journal, volume 3,
Publication date
October 2016
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. Blockageofthese pathwaysmayimprove musclequality andfunction inDMD.Antisenseoligonucleotides(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 musclefiber 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 thatALK4 inhibition increases myogenesisbut also regulates the tight balance of protein synthesisand degradation. Therefore, caution must be used when developing therapies that interfere with MSTN/activin pathways. — Pasteuning-Vuhman, S., Boertje-van der Meulen, J., van Putten, M., Overzier, M., ten Dijke, P., Kie ł basa,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 ty pe I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration. FASEB J. 31, 000 – 000 (2017). www.fasebj.org
DOI link
10.1096/fj.201600675R