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Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy
Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle de...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581601/ https://www.ncbi.nlm.nih.gov/pubmed/26206886 http://dx.doi.org/10.1093/hmg/ddv288 |
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author | Lee, Yun-Sil Lehar, Adam Sebald, Suzanne Liu, Min Swaggart, Kayleigh A. Talbot, C. Conover Pytel, Peter Barton, Elisabeth R. McNally, Elizabeth M. Lee, Se-Jin |
author_facet | Lee, Yun-Sil Lehar, Adam Sebald, Suzanne Liu, Min Swaggart, Kayleigh A. Talbot, C. Conover Pytel, Peter Barton, Elisabeth R. McNally, Elizabeth M. Lee, Se-Jin |
author_sort | Lee, Yun-Sil |
collection | PubMed |
description | Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression. To investigate this possibility, we examined the effect of blocking the myostatin pathway in dysferlin-deficient (Dysf(−/−)) mice, in which membrane repair is compromised, either by transgenic expression of follistatin in skeletal muscle or by systemic administration of the soluble form of the activin type IIB receptor (ACVR2B/Fc). Here, we show that myostatin inhibition by follistatin transgene expression in Dysf(−/−) mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin-deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin. Dysf(−/−) mice injected with ACVR2B/Fc showed significant increases in muscle mass and amelioration of fibrotic changes normally seen in 8-month-old Dysf(−/−) mice. Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(−/−) mice, indicating possible muscle damage induced by hypertrophy. These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis. |
format | Online Article Text |
id | pubmed-4581601 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45816012015-09-25 Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy Lee, Yun-Sil Lehar, Adam Sebald, Suzanne Liu, Min Swaggart, Kayleigh A. Talbot, C. Conover Pytel, Peter Barton, Elisabeth R. McNally, Elizabeth M. Lee, Se-Jin Hum Mol Genet Articles Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression. To investigate this possibility, we examined the effect of blocking the myostatin pathway in dysferlin-deficient (Dysf(−/−)) mice, in which membrane repair is compromised, either by transgenic expression of follistatin in skeletal muscle or by systemic administration of the soluble form of the activin type IIB receptor (ACVR2B/Fc). Here, we show that myostatin inhibition by follistatin transgene expression in Dysf(−/−) mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin-deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin. Dysf(−/−) mice injected with ACVR2B/Fc showed significant increases in muscle mass and amelioration of fibrotic changes normally seen in 8-month-old Dysf(−/−) mice. Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(−/−) mice, indicating possible muscle damage induced by hypertrophy. These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis. Oxford University Press 2015-10-15 2015-07-23 /pmc/articles/PMC4581601/ /pubmed/26206886 http://dx.doi.org/10.1093/hmg/ddv288 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Lee, Yun-Sil Lehar, Adam Sebald, Suzanne Liu, Min Swaggart, Kayleigh A. Talbot, C. Conover Pytel, Peter Barton, Elisabeth R. McNally, Elizabeth M. Lee, Se-Jin Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title | Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title_full | Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title_fullStr | Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title_full_unstemmed | Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title_short | Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
title_sort | muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581601/ https://www.ncbi.nlm.nih.gov/pubmed/26206886 http://dx.doi.org/10.1093/hmg/ddv288 |
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