Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease

Gaelle Douillard-Guilloux, Nina Raben, Shoichi Takikita, Arnaud Ferry, Alban Vignaud, Isabelle Guillet-Deniau, Maryline Favier, Beth L. Thurberg, Peter Roach, Catherine Caillaud, Emmanuel Richard

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.

Original languageEnglish
Article numberddp535
Pages (from-to)684-696
Number of pages13
JournalHuman Molecular Genetics
Volume19
Issue number4
DOIs
StatePublished - Dec 3 2009

Fingerprint

Glycogen Storage Disease Type II
Genetic Suppression
Glycogen
Muscles
Glycogen Synthase
Skeletal Muscle
Myocardium
Enzyme Replacement Therapy
Muscular Atrophy
Hypertrophic Cardiomyopathy
Cardiomegaly
Respiratory Insufficiency
Small Interfering RNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Douillard-Guilloux, G., Raben, N., Takikita, S., Ferry, A., Vignaud, A., Guillet-Deniau, I., ... Richard, E. (2009). Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Human Molecular Genetics, 19(4), 684-696. [ddp535]. https://doi.org/10.1093/hmg/ddp535

Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. / Douillard-Guilloux, Gaelle; Raben, Nina; Takikita, Shoichi; Ferry, Arnaud; Vignaud, Alban; Guillet-Deniau, Isabelle; Favier, Maryline; Thurberg, Beth L.; Roach, Peter; Caillaud, Catherine; Richard, Emmanuel.

In: Human Molecular Genetics, Vol. 19, No. 4, ddp535, 03.12.2009, p. 684-696.

Research output: Contribution to journalArticle

Douillard-Guilloux, G, Raben, N, Takikita, S, Ferry, A, Vignaud, A, Guillet-Deniau, I, Favier, M, Thurberg, BL, Roach, P, Caillaud, C & Richard, E 2009, 'Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease', Human Molecular Genetics, vol. 19, no. 4, ddp535, pp. 684-696. https://doi.org/10.1093/hmg/ddp535
Douillard-Guilloux G, Raben N, Takikita S, Ferry A, Vignaud A, Guillet-Deniau I et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Human Molecular Genetics. 2009 Dec 3;19(4):684-696. ddp535. https://doi.org/10.1093/hmg/ddp535
Douillard-Guilloux, Gaelle ; Raben, Nina ; Takikita, Shoichi ; Ferry, Arnaud ; Vignaud, Alban ; Guillet-Deniau, Isabelle ; Favier, Maryline ; Thurberg, Beth L. ; Roach, Peter ; Caillaud, Catherine ; Richard, Emmanuel. / Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. In: Human Molecular Genetics. 2009 ; Vol. 19, No. 4. pp. 684-696.
@article{192c569892644a13acef1859637a271a,
title = "Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease",
abstract = "Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.",
author = "Gaelle Douillard-Guilloux and Nina Raben and Shoichi Takikita and Arnaud Ferry and Alban Vignaud and Isabelle Guillet-Deniau and Maryline Favier and Thurberg, {Beth L.} and Peter Roach and Catherine Caillaud and Emmanuel Richard",
year = "2009",
month = "12",
day = "3",
doi = "10.1093/hmg/ddp535",
language = "English",
volume = "19",
pages = "684--696",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease

AU - Douillard-Guilloux, Gaelle

AU - Raben, Nina

AU - Takikita, Shoichi

AU - Ferry, Arnaud

AU - Vignaud, Alban

AU - Guillet-Deniau, Isabelle

AU - Favier, Maryline

AU - Thurberg, Beth L.

AU - Roach, Peter

AU - Caillaud, Catherine

AU - Richard, Emmanuel

PY - 2009/12/3

Y1 - 2009/12/3

N2 - Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.

AB - Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.

UR - http://www.scopus.com/inward/record.url?scp=77950342469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950342469&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp535

DO - 10.1093/hmg/ddp535

M3 - Article

C2 - 19959526

AN - SCOPUS:77950342469

VL - 19

SP - 684

EP - 696

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

M1 - ddp535

ER -