Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF/CCN2), which induces their dedifferentiation.
Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes of different tissues. Connective tissue growth factor (CTGF) seems to be involved in the fibrotic response. Several muscular dystrophies are characterized by a progressive weakness and wasting of the musculature, and by extensive fibrosis. However, the exact role of CTGF in skeletal muscle is unknown. Here we show that myoblasts and myotubes are able to synthesize CTGF in response to transforming growth factor type-beta (TGF-beta) and lysophosphatidic acid (LPA). CTGF induced several ECM constituents such as fibronectin, collagen type I and alpha4, 5, 6, and beta1 integrin subunits in myoblasts and myotubes. CTGF had an important inhibitory effect on muscle differentiation evaluated by the decrease in the nuclear translocation of the early muscle regulatory factor myogenin and myosin. Remarkable, CTGF treatment of myoblasts induced their dedifferentiation, characterized by down regulating MyoD and desmin, two markers of committed myoblasts, together with a strong reorganization of cytoskeletal filaments. These results provide novel evidence for the underlying mechanisms and participation of skeletal muscle cells in the synthesis and role of CTGF inducing fibrosis, inhibiting myogenesis and dedifferentiating myoblasts.
Centro de Regulación y Patología Joaquín V. Luco, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, MIFAB, Santiago, Chile.
Cecilia
C
Vial
Lidia Miriam
LM
Zúñiga
Claudio
C
Cabello-Verrugio
Pablo
P
Cañón
Ricardo
R
Fadic
Enrique
E
Brandan
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D054337:Cell Dedifferentiation; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003599:Cytoskeleton / Q000187:drug effects; D003893:Desmin / Q000378:metabolism; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526318:CCN2 protein, mouse; D003893:Desmin; D016326:Extracellular Matrix Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D017570:MyoD Protein; D018008:Myogenin; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D009218:Myosins; C032881:lysophosphatidic acid