ADAM12 Alleviates the Skeletal Muscle Pathology in mdx Dystrophic Mice

Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar; Xu, Xiufeng; Schrøder, Henrik Daa; Moghadaszadeh, Behzad; Nielsen, Finn Cilius; Fröhlich, Camilla; Engvall, Eva; Wewer, Ulla M.

doi:10.1016/s0002-9440(10)64431-8

Cited by 60 publications

(49 citation statements)

References 43 publications

(55 reference statements)

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“…Since no alterations in transcription of the genes encoding the components of the dystrophin glycoprotein complex were observed in both array analyses, it is likely that the enhanced structural linkage and signaling provided by increased integrin accounts for the alleviation of dystrophic pathology in ␣ 7 -transgenic mdx/utrn Ϫ/Ϫ mice (12, 13). Array analysis of ADAM12 transgenic mice, in which an increase in ADAM12 partially rescued mdx mice, reported an increase of ␣ 7 -protein but not mRNA in skeletal muscle (41,51). In both our cell and tissue arrays, no significant change in transcription of any of the ADAM genes was detected, which suggests that ␣ 7 ␤ 1 -integrin may function downstream or in concert with ADAM12 in promoting muscle regeneration and preventing muscular dystrophy.…”

Section: Inducible Expression and Localization Of ␣ 7 -Integrin In C2mentioning

confidence: 51%

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Liu

Burkin²,

Kaufman

2008

American Journal of Physiology-Cell Physiology

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Liu J, Burkin DJ, Kaufman SJ. Increasing ␣7␤1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. Am J Physiol Cell Physiol 294: C627-C640, 2008. First published November 28, 2007 doi:10.1152/ajpcell.00329.2007.-The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The ␣ 7␤1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of ␣ 7-integrin levels alleviates pathology in mdx/utrn Ϫ/Ϫ mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing ␣ 7-integrin levels affects transcription and cellular functions, we generated ␣ 7-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of ␣ 7-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy. myoblast proliferation; integrin transgenic mice; microarray CELLS CAN RECOGNIZE AND INTERACT with their environment through membrane receptors specific for different extracellular matrix proteins. The heterodimeric integrins are evolutionarily conserved receptors for matrix proteins found in all metazoans (37). In skeletal muscle, the association of the extracellular matrix with the cytoskeleton is essential for maintaining the integrity of the sarcolemma, sustaining appropriate myofiber architecture, and correctly transmitting the forces produced by muscle contractions (5, 42). The ␣ 7 ␤ 1 -integrin is part of a linkage system that maintains such transmembrane associations in skeletal muscle (10,66). It binds to laminin in the basal lamina that surrounds muscle fibers. Within muscle fibers, the integrin associates with the subsarcolemmal cytoskeleton network through focal adhesion complexes (5). The ␣ 7 ␤ 1 -integrin is distributed along the sarcolemma at costameres, and it is also concentrated at neuromuscular and myotendinous junctions (2,48). This localization suggests that the integrin has a pivotal role in maintaining these specialized structures and their functions in skeletal muscle. Congenital myopathies caused by mutations in t...

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Section: Inducible Expression and Localization Of ␣ 7 -Integrin In C2mentioning

confidence: 51%

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Liu

Burkin²,

Kaufman

2008

American Journal of Physiology-Cell Physiology

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“…The secreted form ADAM12-S can cleave insulin-like growth factor (IGF)-binding protein-3 and -5 Shi et al, 2000), and in so doing promotes bioactivity of IGF-1 and -2, two positive regulators of muscle growth, survival, and regeneration (Husmann et al, 1996;Kaliman et al, 1996;Kronqvist et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In rodents, constitutive muscle expression of ADAM12 starts at the embryonic stage when myotubes are formed (Kurisaki et al, 1998), persists at the neonatal stage (Yagami-Hiromasa et al, 1995;Borneman et al, 2000;Kronqvist et al, 2002), and ceases in adulthood (Borneman et al, 2000;Kronqvist et al, 2002). Adult muscle regeneration after experimental injury is associated with ADAM12 reexpression by fusing myogenic cells and newly formed fibers (Galliano et al, 2000;Kronqvist et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Lafuste

Sonnet

Chazaud

et al. 2005

MBoC

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Knowledge on molecular systems involved in myogenic precursor cell (mpc) fusion into myotubes is fragmentary. Previous studies have implicated the a disintegrin and metalloproteinase (ADAM) family in most mammalian cell fusion processes. ADAM12 is likely involved in fusion of murine mpc and human rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion. ADAM12 was shown able to mediate cell-to-cell attachment through binding ␣ 9 ␤ 1 integrin. We report that normal human mpc express both ADAM12 and ␣ 9 ␤ 1 integrin during their differentiation. Expression of ␣ 9 parallels that of ADAM12 and culminates at time of fusion. ␣ 9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/␣ 9 ␤ 1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to ␣ 9 ␤ 1 , inhibited overall mpc fusion by 47-48%, with combination of both strategies increasing inhibition up to 62%. By contrast with blockade of vascular cell adhesion molecule-1/␣ 4 ␤ 1 , which also reduced fusion, exposure to ADAM12 antisense oligonucleotides or anti-␣ 9 ␤ 1 antibody did not induce detachment of mpc from extracellular matrix, suggesting specific involvement of ADAM12-␣ 9 ␤ 1 interaction in the fusion process. Evaluation of the fusion rate with regard to the size of myotubes showed that both ADAM12 antisense oligonucleotides and ␣ 9 ␤ 1 blockade inhibited more importantly formation of large (>5 nuclei) myotubes than that of small (2-4 nuclei) myotubes. We conclude that both ADAM12 and ␣ 9 ␤ 1 integrin are expressed during postnatal human myogenic differentiation and that their interaction is mainly operative in nascent myotube growth. INTRODUCTIONAdult skeletal muscle regeneration after injury results from activation, proliferation, and fusion of mononucleated myogenic precursor cells (mpc) (Hawke and Garry, 2001). The mpc fusion results from an ordered sequence of events, including clustering and alignment of cells, establishment of close cell-to-cell contacts, and plasma membrane merging (Doberstein et al., 1997;Taylor, 2003). Various membrane proteins have been implicated in myotube formation, including N-and M-cadherins, neural cell adhesion molecule (NCAM), and vascular cell adhesion molecule (VCAM), ␣ 4 ␤ 1 and other integrins, and a disintegrin and metalloproteinases (ADAMs) (Abmayr et al., 2003). ADAMs form a family of Ͼ30 transmembrane glycoproteins with a unique domain organization, including a prodomain, a proteolytic domain (metalloprotease), an adhesion integrin-binding site formed by both disintegrin and cysteine-rich domains, an epidermal growth factor-like domain, a transmembrane domain, and a signaling cytoplasmic tail (Huovila et al., 1996;Primakoff and Myles, 2002;White, 2003). In addition, some ADAMs contain a hydrophobic sequence in a cysteine-rich region that may represent a fusion peptide, suggesting that this subclass of ADAMs might participate to plasma membrane merging (Huovila et al., 1996). Some ADAMs have been implicated i...

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“…ADAM12, originally named meltrin-␣ (25), has been implicated in muscle cell function in vivo and in vitro (25)(26)(27)(28)(29)(30). In the original study, expression of a truncated version of ADAM12, lacking the prodomain and metalloprotease domain, was found to stimulate muscle-cell fusion in cultured C2C12 cells, whereas full-length ADAM12 inhibited the fusion process (25).…”

mentioning

confidence: 99%

“…The level of cell-surface ADAM12 seemed to be highest at the onset of differentiation. These and other studies have demonstrated that ADAM12 has a specific temporal expression pattern in several tissue compartments during development, regeneration, and in disease (12,18,19,(23)(24)(25)(26)(27)(28)(29)(30)33). However, little is known about the regulation of ADAM12 activation and translocation to the cell surface.…”

mentioning

confidence: 99%

Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ϵ

Sundberg

Thodeti

Kveiborg

et al. 2004

Journal of Biological Chemistry

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The ADAM (a disintegrin and metalloprotease) family consists of multidomain cell-surface proteins that have a major impact on cell behavior. These transmembraneanchored proteins are synthesized as proforms that have (from the N terminus): a prodomain; a metalloprotease-, disintegrin-like-, cysteine-rich, epidermal growth factor-like, and transmembrane domain; and a cytoplasmic tail. The 90-kDa mature form of human ADAM12 is generated in the trans-Golgi through cleavage of the prodomain by a furin-peptidase and is stored intracellularly until translocation to the cell surface as a constitutively active protein. However, little is known about the regulation of ADAM12 cell-surface translocation. Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern. We report that protein kinase C (PKC) ⑀ induces ADAM12 translocation to the cell surface and that catalytic activity of PKC⑀ is required for this translocation. Cells possess a diverse array of surface proteins, lipids, and carbohydrates that provide active gateways for the selective intake and release of molecular information, which is important in regulating cell behavior. In fact, many disease processes relate to disorganized cell-surface communication systems. ADAMs 1 belong to a large family of cell-surface proteins with over 30 members. The prototypical ADAM molecule is a transmembrane glycoprotein composed of several distinct domains, including a prodomain and a metalloprotease, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domain. ADAMs play important roles in cell adhesion, interacting with integrins and syndecans, and in the proteolysis of the ectodomains of cell-surface proteins,

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ADAM12 Alleviates the Skeletal Muscle Pathology in mdx Dystrophic Mice

Cited by 60 publications

References 43 publications

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ϵ

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ADAM12 Alleviates the Skeletal Muscle Pathology in mdx Dystrophic Mice

Cited by 60 publications

References 43 publications

Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

ADAM12 and α9β1Integrin Are Instrumental in Human Myogenic Cell Differentiation

Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ϵ

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Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation