Improved success of myoblast transplantation in mdx mice by blocking the myostatin signal

被引:36
作者
Benabdallah, BF [1 ]
Bouchentouf, M [1 ]
Tremblay, JP [1 ]
机构
[1] Univ Laval, Unite Rech & Genet Humaine, CHUQ, Dept Human Genet,CHU Laval, Quebec City, PQ G1V 4G2, Canada
关键词
Duchenne muscular dystrophy; myoblast transplantation; graft success; myostatin;
D O I
10.1097/01.TP.0000167379.27872.2B
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Duchenne muscular dystrophy (DMD) is caused by a dystrophin gene mutation. Transplantation of normal myoblasts results in long-term restoration of dystrophin. However, the success of this approach is compromised by the limited time of regeneration following muscle damage. Myostatin is known to be responsible for limiting skeletal muscle regeneration. Our purpose is to verify whether blocking the myostatin signal in mdx host mice or in normal myoblasts transplanted in mdx host mice would increase the extent of muscle repair and thus allow the formation of more dystrophin-positive fibers. Methods. Transgenic mdx mice carrying a dominant negative form of myostatin receptor (dnActRIIB) were used to test the fiber resistance to damage and to act as a host for normal myoblast transplantation. Myoblasts obtained from nondystrophic transgenic mice carrying the dominant negative myostatin receptor were also transplanted in nontransgenic mdx mice. Results. Transgenic mdx mice carrying the dnActRIIB gene have bigger muscles than mdx mice with the normal gene of ActRIIB. Their fiber resistance to exercise-induced damage was also greatly improved. Moreover, the success of normal myoblast transplantation was significantly enhanced in mdx/dnActRIIB mice. Finally, nondystrophic dnActRIIB myoblasts formed more abundant and bigger dystrophin positive fibers when transplanted in mdx mice. Conclusions. Blocking the myostatin signal in mdx mice allowed the size of muscle fibers to increase, the fiber resistance to damage induced by exercise to increase, and the success of normal myoblast transplantation to improve. The transplantation in mdx mice of dnActRIIB myoblasts formed more abundant and larger dystrophin positive fibers.
引用
收藏
页码:1696 / 1702
页数:7
相关论文
共 32 条
[1]   DEFECTIVE MYOBLASTS IDENTIFIED IN DUCHENNE MUSCULAR-DYSTROPHY [J].
BLAU, HM ;
WEBSTER, C ;
PAVLATH, GK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (15) :4856-4860
[2]   Functional improvement of dystrophic muscle by myostatin blockade [J].
Bogdanovich, S ;
Krag, TOB ;
Barton, ER ;
Morris, LD ;
Whittemore, LA ;
Ahima, RS ;
Khurana, TS .
NATURE, 2002, 420 (6914) :418-421
[3]   Muscle fibers of mdx mice are more vulnerable to exercise than those of normal mice [J].
Brussee, V ;
Tardif, F ;
Tremblay, JP .
NEUROMUSCULAR DISORDERS, 1997, 7 (08) :487-492
[4]   DUCHENNE MUSCULAR-DYSTROPHY - MERYONS DISEASE [J].
EMERY, AEH .
NEUROMUSCULAR DISORDERS, 1993, 3 (04) :263-266
[5]  
GIOS R, 2002, AM J PHYSIOL-CELL PH, V282, pC993
[6]   A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle [J].
Grobet, L ;
Martin, LJR ;
Poncelet, D ;
Pirottin, D ;
Brouwers, B ;
Riquet, J ;
Schoeberlein, A ;
Dunner, S ;
Menissier, F ;
Massabanda, J ;
Fries, R ;
Hanset, R ;
Georges, M .
NATURE GENETICS, 1997, 17 (01) :71-74
[7]   Evans Blue Dye as an in vivo marker of myofibre damage:: optimising parameters for detecting initial myofibre membrane permeability [J].
Hamer, PW ;
McGeachie, JM ;
Davies, MJ ;
Grounds, MD .
JOURNAL OF ANATOMY, 2002, 200 (01) :69-79
[8]   DYSTROPHIN - THE PROTEIN PRODUCT OF THE DUCHENNE MUSCULAR-DYSTROPHY LOCUS [J].
HOFFMAN, EP ;
BROWN, RH ;
KUNKEL, LM .
CELL, 1987, 51 (06) :919-928
[9]   Transplantation of dermal fibroblasts expressing MyoD1 in mouse muscles [J].
Huard, C ;
Moisset, PA ;
Dicaire, A ;
Merly, F ;
Tardif, F ;
Asselin, I ;
Tremblay, JP .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 248 (03) :648-654
[10]   GENE-TRANSFER INTO SKELETAL-MUSCLES BY ISOGENIC MYOBLASTS [J].
HUARD, J ;
ACSADI, G ;
JANI, A ;
MASSIE, B ;
KARPATI, G .
HUMAN GENE THERAPY, 1994, 5 (08) :949-958