Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy

Yun Sil Lee, Adam Lehar, Suzanne Sebald, Min Liu, Kayleigh A. Swaggart, C. Conover Talbot, Peter Pytel, Elisabeth R. Barton, Elizabeth M. McNally, Se Jin Lee

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 targetingmyostatin 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 showthatmyostatin 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 dystrophindeficient (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.

Original languageEnglish (US)
Pages (from-to)5711-5719
Number of pages9
JournalHuman molecular genetics
Issue number20
StatePublished - Jun 5 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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