A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Brett M. Morrison; Jennifer L. Lachey; Leigh C. Warsing; Beverlie L. Ting; Abigail E. Pullen; Kathryn W. Underwood; Ravindra Kumar; Dianne Sako; Asya Grinberg; Vicki Wong; Elizabeth Colantuoni; Jasbir S. Seehra; Kathryn R. Wagner

doi:10.1016/j.expneurol.2009.02.017

A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Brett M. Morrison, Jennifer L. Lachey, Leigh C. Warsing, Beverlie L. Ting, Abigail E. Pullen, Kathryn W. Underwood, Ravindra Kumar, Dianne Sako, Asya Grinberg, Vicki Wong, Elizabeth Colantuoni, Jasbir S. Seehra, Kathryn R. Wagner

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-β superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1^G93A transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-β superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1^G93A transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1^G93A transgenic mice. The improved function of SOD1^G93A transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-β pathway inhibitors to increase muscle strength in patients with ALS.

Original language	English (US)
Pages (from-to)	258-268
Number of pages	11
Journal	Experimental Neurology
Volume	217
Issue number	2
DOIs	https://doi.org/10.1016/j.expneurol.2009.02.017
State	Published - Jun 2009

Keywords

ALS
Activin receptor
Muscle
Myostatin
SOD1
Treatment

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

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10.1016/j.expneurol.2009.02.017

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Morrison, B. M., Lachey, J. L., Warsing, L. C., Ting, B. L., Pullen, A. E., Underwood, K. W., Kumar, R., Sako, D., Grinberg, A., Wong, V., Colantuoni, E., Seehra, J. S., & Wagner, K. R. (2009). A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis. Experimental Neurology, 217(2), 258-268. https://doi.org/10.1016/j.expneurol.2009.02.017

Morrison, BM, Lachey, JL, Warsing, LC, Ting, BL, Pullen, AE, Underwood, KW, Kumar, R, Sako, D, Grinberg, A, Wong, V, Colantuoni, E, Seehra, JS & Wagner, KR 2009, 'A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis', Experimental Neurology, vol. 217, no. 2, pp. 258-268. https://doi.org/10.1016/j.expneurol.2009.02.017

@article{c674dd3ba4604883a3d3ea7d9cd8bada,

title = "A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis",

abstract = "Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-β superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1G93A transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-β superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1G93A transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1G93A transgenic mice. The improved function of SOD1G93A transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-β pathway inhibitors to increase muscle strength in patients with ALS.",

keywords = "ALS, Activin receptor, Muscle, Myostatin, SOD1, Treatment",

author = "Morrison, {Brett M.} and Lachey, {Jennifer L.} and Warsing, {Leigh C.} and Ting, {Beverlie L.} and Pullen, {Abigail E.} and Underwood, {Kathryn W.} and Ravindra Kumar and Dianne Sako and Asya Grinberg and Vicki Wong and Elizabeth Colantuoni and Seehra, {Jasbir S.} and Wagner, {Kathryn R.}",

note = "Funding Information: This study was supported by The Passano Foundation (B.M.M.), Muscular Dystrophy Association (B.M.M.), The Packard Center for ALS Research (K.R.W.) and Acceleron Pharma, Inc. (J.L.L., A.E.P., K.W.U., R.K., D.S., A.G., V.W., and J.S.S.). J.L.L., A.E.P., K.W.U., R.K., D.S., A.G., V.W., and J.S.S. are employees of and have equity in Acceleron Pharma, Inc. We acknowledge Amy Andreucci, Jeffrey Ucran, Eileen Pobre and Travis Monnell of Acceleron Pharma, Inc. for production of RAP-031. We also thank Se-Jin Lee for myostatin null animals and support of initial investigations. ",

year = "2009",

month = jun,

doi = "10.1016/j.expneurol.2009.02.017",

language = "English (US)",

volume = "217",

pages = "258--268",

journal = "Experimental Neurology",

issn = "0014-4886",

publisher = "Academic Press Inc.",

number = "2",

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TY - JOUR

T1 - A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

AU - Morrison, Brett M.

AU - Lachey, Jennifer L.

AU - Warsing, Leigh C.

AU - Ting, Beverlie L.

AU - Pullen, Abigail E.

AU - Underwood, Kathryn W.

AU - Kumar, Ravindra

AU - Sako, Dianne

AU - Grinberg, Asya

AU - Wong, Vicki

AU - Colantuoni, Elizabeth

AU - Seehra, Jasbir S.

AU - Wagner, Kathryn R.

N1 - Funding Information: This study was supported by The Passano Foundation (B.M.M.), Muscular Dystrophy Association (B.M.M.), The Packard Center for ALS Research (K.R.W.) and Acceleron Pharma, Inc. (J.L.L., A.E.P., K.W.U., R.K., D.S., A.G., V.W., and J.S.S.). J.L.L., A.E.P., K.W.U., R.K., D.S., A.G., V.W., and J.S.S. are employees of and have equity in Acceleron Pharma, Inc. We acknowledge Amy Andreucci, Jeffrey Ucran, Eileen Pobre and Travis Monnell of Acceleron Pharma, Inc. for production of RAP-031. We also thank Se-Jin Lee for myostatin null animals and support of initial investigations.

PY - 2009/6

Y1 - 2009/6

N2 - Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-β superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1G93A transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-β superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1G93A transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1G93A transgenic mice. The improved function of SOD1G93A transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-β pathway inhibitors to increase muscle strength in patients with ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-β superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1G93A transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-β superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1G93A transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1G93A transgenic mice. The improved function of SOD1G93A transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-β pathway inhibitors to increase muscle strength in patients with ALS.

KW - ALS

KW - Activin receptor

KW - Muscle

KW - Myostatin

KW - SOD1

KW - Treatment

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SN - 0014-4886

VL - 217

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JO - Experimental Neurology

JF - Experimental Neurology

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ER -

A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Abstract

Keywords

ASJC Scopus subject areas

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