Cloning of cDNA encoding a regeneration-associated muscle protease whose expression is attenuated in cell lines derived from Duchenne muscular dystrophy patients.

In the dystrophin-mutant mdx mouse, an animal model for Duchenne muscular dystrophy (DMD), damaged skeletal muscles are efficiently regenerated and thus the animals thrive. The phenotypic differences between DMD patients and the mdx mice suggest the existence of factors that modulate the muscle wasting in the mdx mice. To identify these factors, we searched for mRNAs affected by the mdx mutation by using cDNA microarrays with newly established skeletal muscle cell lines from mdx and normal mice. We found that in the mdx muscle cell line, 12 genes, including L-arginine:glycine amidinotransferase and thymosin beta4, are up-regulated, whereas 7 genes, including selenoprotein P and a novel regeneration-associated muscle protease (RAMP), are down-regulated. Northern blot analysis and in situ hybridization revealed that RAMP mRNA is predominantly expressed in normal skeletal muscle and brain, and its production is enhanced in the regenerating area of injured skeletal muscle in mice. RAMP expression was much lower in individual muscle cell lines derived from biopsies of six DMD patients compared to a normal muscle cell line. These results suggest that RAMP may play a role in the regeneration of skeletal muscle and that its down-regulation could be involved in the progression of DMD in humans.

[1]  A. Otto,et al.  beta-Thymosins, small acidic peptides with multiple functions. , 2001, The international journal of biochemistry & cell biology.

[2]  S. Gordon,et al.  Regenerated mdx mouse skeletal muscle shows differential mRNA expression. , 2002, Journal of applied physiology.

[3]  G. Vrbóva,et al.  Muscle development in mdx mutant mice , 1984, Muscle & nerve.

[4]  J. D. Porter,et al.  A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. , 2002, Human molecular genetics.

[5]  F. Muntoni,et al.  Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome , 2001, Nature Genetics.

[6]  K. Aldape,et al.  Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy , 1995, Cell.

[7]  K. Ge,et al.  Keshan disease-an endemic cardiomyopathy in China , 2004, Virchows Archiv A.

[8]  C. Prives,et al.  The transforming activity of simian virus 40 large tumor antigen. , 1994, Biochimica et biophysica acta.

[9]  E. Papadimitriou,et al.  The tetrapeptide AcSDKP, an inhibitor of primitive hematopoietic cell proliferation, induces angiogenesis in vitro and in vivo. , 2003, Blood.

[10]  G. Dickson,et al.  Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene. , 2002, Biochemical and biophysical research communications.

[11]  M. Hagiwara,et al.  Controlled gene expression with a reverse tetracycline-regulated retroviral vector (RTRV) system. , 1997, Biochemical and biophysical research communications.

[12]  M. Rudnicki,et al.  Activation of JNK1 contributes to dystrophic muscle pathogenesis , 2001, Current Biology.

[13]  Dongsheng Duan,et al.  Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy , 2002, Nature Medicine.

[14]  J. Léger,et al.  Large-scale analysis of differential gene expression in the hindlimb muscles and diaphragm of mdx mouse. , 2000, Biochimica et biophysica acta.

[15]  T. Kitamura,et al.  Plat-E: an efficient and stable system for transient packaging of retroviruses , 2000, Gene Therapy.

[16]  G. Pavlath,et al.  Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells. , 1998, Molecular biology of the cell.

[17]  Eric P. Hoffman,et al.  Expression Profiling in the Muscular Dystrophies Identification of Novel Aspects of Molecular Pathophysiology , 2000 .

[18]  M. Le Cunff,et al.  Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice. , 2002, American journal of physiology. Cell physiology.

[19]  J. Ervasti,et al.  Membrane organization of the dystrophin-glycoprotein complex , 1991, Cell.

[20]  A. Musarò,et al.  Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice , 2002, The Journal of cell biology.

[21]  A. Miyajima,et al.  Distinct roles of oncostatin M and leukemia inhibitory factor in the development of primordial germ cells and sertoli cells in mice. , 1998, Developmental biology.

[22]  R. Ahima,et al.  Functional improvement of dystrophic muscle by myostatin blockade , 2002, Nature.

[23]  G. Pavlath,et al.  IL-4 Acts as a Myoblast Recruitment Factor during Mammalian Muscle Growth , 2003, Cell.

[24]  K. Moore,et al.  X chromosome-linked muscular dystrophy (mdx) in the mouse. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Ogawa,et al.  Conditional transformation of mouse liver epithelial cells. An in vitro model for analysis of genetic events in hepatocarcinogenesis. , 1995, The American journal of pathology.

[26]  H. Sweeney,et al.  Dystrophin protects the sarcolemma from stresses developed during muscle contraction. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Cooper,et al.  Reversible immortalization of human myogenic cells by site-specific excision of a retrovirally transferred oncogene. , 1999, Human gene therapy.

[28]  J. Ervasti,et al.  Dystrophin and the membrane skeleton. , 1993, Current opinion in cell biology.

[29]  A. Goldstein,et al.  Thymosin β4 stimulates directional migration of human umbilical vein endothelial cells , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  L. Kunkel,et al.  Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Bork,et al.  The CUB domain. A widespread module in developmentally regulated proteins. , 1993, Journal of molecular biology.

[32]  C. Bucana,et al.  Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. , 1997, Science.

[33]  V. Mostert.  Selenoprotein P: properties, functions, and regulation. , 2000, Archives of biochemistry and biophysics.

[34]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.

[35]  Y. Masuho,et al.  Isolation of novel mouse genes differentially expressed in brain using cDNA microarray. , 2000, Biochemical and biophysical research communications.

[36]  A. Mamalaki,et al.  Isolation of a mouse brain cDNA expressed in developing neuroblasts and mature neurons. , 2001, Brain research. Molecular brain research.

[37]  G. Butler-Browne,et al.  SV40 large T antigen interferes with adult myosin heavy chain expression, but not with differentiation of human satellite cells. , 1996, Experimental cell research.

[38]  N. Rawlings,et al.  Evolutionary families of peptidases. , 1993, The Biochemical journal.

[39]  E A Barnard,et al.  The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. , 1989, Science.

[40]  Jacques Camonis,et al.  Cloning and Characterization of SCHIP-1, a Novel Protein Interacting Specifically with Spliced Isoforms and Naturally Occurring Mutant NF2 Proteins , 2000, Molecular and Cellular Biology.

[41]  I. Campbell,et al.  Three-dimensional structure of a complement control protein module in solution. , 1991, Journal of molecular biology.

[42]  H. Herschman,et al.  The glucocorticoid attenuated response genes GARG-16, GARG-39, and GARG-49/IRG2 encode inducible proteins containing multiple tetratricopeptide repeat domains. , 1996, Archives of biochemistry and biophysics.

[43]  Mildred A. Carlson,et al.  S-Adenosylmethionine: Guanidinoacetate N-Methyltransferase Activities in Livers from Rats with Hormonal Deficiencies or Excesses 1 , 1973, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[44]  G. von Heijne,et al.  Signal sequences: The limits of variation , 1985 .

[45]  J. Molkentin,et al.  A Calcineurin-NFATc3-Dependent Pathway Regulates Skeletal Muscle Differentiation and Slow Myosin Heavy-Chain Expression , 2000, Molecular and Cellular Biology.

[46]  R. Stevenson,et al.  Thymosin β 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids , 1999, Nature Medicine.

[47]  J. Boen,et al.  Cloning and sequencing of rat kidney L-arginine:glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. , 1994, The Journal of biological chemistry.

[48]  Y. Masuho,et al.  cDNA microarray analysis of Helicobacter pylori-mediated alteration of gene expression in gastric cancer cells. , 2001, Biochemical and biophysical research communications.

[49]  W. Denetclaw,et al.  Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin. , 1990, Science.