Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 5711-5719 |
| Number of pages | 9 |
| Journal | Human Molecular Genetics |
| Volume | 24 |
| Issue number | 20 |
| DOIs | |
| State | Published - Jun 5 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy. / Lee, Yun Sil; Lehar, Adam; Sebald, Suzanne; Liu, Min; Swaggart, Kayleigh A.; Conover Talbot, C.; Pytel, Peter; Barton, Elisabeth R.; McNally, Elizabeth M.; Lee, Se Jin.
In: Human Molecular Genetics, Vol. 24, No. 20, 05.06.2015, p. 5711-5719.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy
AU - Lee, Yun Sil
AU - Lehar, Adam
AU - Sebald, Suzanne
AU - Liu, Min
AU - Swaggart, Kayleigh A.
AU - Conover Talbot, C.
AU - Pytel, Peter
AU - Barton, Elisabeth R.
AU - McNally, Elizabeth M.
AU - Lee, Se Jin
PY - 2015/6/5
Y1 - 2015/6/5
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddv288
DO - 10.1093/hmg/ddv288
M3 - Article
C2 - 26206886
AN - SCOPUS:84943804865
VL - 24
SP - 5711
EP - 5719
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 20
ER -