Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

Joe N. Kornegay, Daniel J. Bogan, Janet R. Bogan, Jennifer L. Dow, Jiahui Wang, Zheng Fan, Naili Liu, Leigh C. Warsing, Robert W. Grange, Mihye Ahn, Cynthia J. Balog-Alvarez, Steven W. Cotten, Monte S. Willis, Candice Brinkmeyer-Langford, Hongtu Zhu, Joe Palandra, Carl A. Morris, Martin A. Styner, Kathryn R. Wagner

Research output: Contribution to journalArticle

Abstract

Background: Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods: To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/-) whippets. A total of four GRippets (dystrophic and Mstn +/-), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results: Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3years of age. Conclusions: Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors.

Original languageEnglish (US)
Article number14
JournalSkeletal Muscle
Volume6
Issue number1
DOIs
StatePublished - Apr 4 2016

Fingerprint

Myostatin
Dystrophin
Contracture
Dogs
Muscles
Muscular Dystrophies
Inbred mdx Mouse
Activin Receptors
Atrophy
Fibrosis
Magnetic Resonance Imaging
Proteins
Quadriceps Muscle
Hypertrophy
Canidae
Regeneration
Down-Regulation
Clinical Trials
RNA
Phenotype

Keywords

  • Contractures
  • Dogs
  • Golden retriever muscular dystrophy (GRMD)
  • Muscle hypertrophy
  • Muscular dystrophy
  • Myostatin inhibition
  • Whippets

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine

Cite this

Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures. / Kornegay, Joe N.; Bogan, Daniel J.; Bogan, Janet R.; Dow, Jennifer L.; Wang, Jiahui; Fan, Zheng; Liu, Naili; Warsing, Leigh C.; Grange, Robert W.; Ahn, Mihye; Balog-Alvarez, Cynthia J.; Cotten, Steven W.; Willis, Monte S.; Brinkmeyer-Langford, Candice; Zhu, Hongtu; Palandra, Joe; Morris, Carl A.; Styner, Martin A.; Wagner, Kathryn R.

In: Skeletal Muscle, Vol. 6, No. 1, 14, 04.04.2016.

Research output: Contribution to journalArticle

Kornegay, JN, Bogan, DJ, Bogan, JR, Dow, JL, Wang, J, Fan, Z, Liu, N, Warsing, LC, Grange, RW, Ahn, M, Balog-Alvarez, CJ, Cotten, SW, Willis, MS, Brinkmeyer-Langford, C, Zhu, H, Palandra, J, Morris, CA, Styner, MA & Wagner, KR 2016, 'Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures' Skeletal Muscle, vol 6, no. 1, 14. DOI: 10.1186/s13395-016-0085-7
Kornegay JN, Bogan DJ, Bogan JR, Dow JL, Wang J, Fan Z et al. Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures. Skeletal Muscle. 2016 Apr 4;6(1). 14. Available from, DOI: 10.1186/s13395-016-0085-7

Kornegay, Joe N.; Bogan, Daniel J.; Bogan, Janet R.; Dow, Jennifer L.; Wang, Jiahui; Fan, Zheng; Liu, Naili; Warsing, Leigh C.; Grange, Robert W.; Ahn, Mihye; Balog-Alvarez, Cynthia J.; Cotten, Steven W.; Willis, Monte S.; Brinkmeyer-Langford, Candice; Zhu, Hongtu; Palandra, Joe; Morris, Carl A.; Styner, Martin A.; Wagner, Kathryn R. / Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures.

In: Skeletal Muscle, Vol. 6, No. 1, 14, 04.04.2016.

Research output: Contribution to journalArticle

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abstract = "Background: Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods: To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/-) whippets. A total of four GRippets (dystrophic and Mstn +/-), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results: Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3years of age. Conclusions: Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors.",
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year = "2016",
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T1 - Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

AU - Kornegay,Joe N.

AU - Bogan,Daniel J.

AU - Bogan,Janet R.

AU - Dow,Jennifer L.

AU - Wang,Jiahui

AU - Fan,Zheng

AU - Liu,Naili

AU - Warsing,Leigh C.

AU - Grange,Robert W.

AU - Ahn,Mihye

AU - Balog-Alvarez,Cynthia J.

AU - Cotten,Steven W.

AU - Willis,Monte S.

AU - Brinkmeyer-Langford,Candice

AU - Zhu,Hongtu

AU - Palandra,Joe

AU - Morris,Carl A.

AU - Styner,Martin A.

AU - Wagner,Kathryn R.

PY - 2016/4/4

Y1 - 2016/4/4

N2 - Background: Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods: To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/-) whippets. A total of four GRippets (dystrophic and Mstn +/-), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results: Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3years of age. Conclusions: Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors.

AB - Background: Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods: To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/-) whippets. A total of four GRippets (dystrophic and Mstn +/-), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results: Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3years of age. Conclusions: Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors.

KW - Contractures

KW - Dogs

KW - Golden retriever muscular dystrophy (GRMD)

KW - Muscle hypertrophy

KW - Muscular dystrophy

KW - Myostatin inhibition

KW - Whippets

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