期刊
ENDOCRINOLOGY
卷 155, 期 3, 页码 670-675出版社
ENDOCRINE SOC
DOI: 10.1210/en.2013-2107
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资金
- National Science Foundation [1147275]
- National Institutes of Health [R01GM084186]
- Muscular Dystrophy Association [216602, 240087]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1147275] Funding Source: National Science Foundation
The immortal C2C12 cell line originates from dystrophicmousethigh muscle and has been used to study the endocrine control of muscle cell growth, development, and function, including those actions regulated by myostatin. Previous studies suggest that high concentrations of recombinant myostatin generated in bacteria inhibit C2C12 proliferation and differentiation. Recombinant myostatin generated in eukaryotic systems similarly inhibits the proliferation of primary myosatellite cells, but consequently initiates, rather than inhibits, their differentiation and is bioactive at far lower concentrations. Our studies indicate that 2 different sources of recombinant myostatin made in eukaryotes stimulate, not inhibit, C2C12 proliferation. This effect occurred at different cell densities and serum concentrations and in the presence of IGF-I, a potent myoblast mitogen. This stimulatory effect was comparable to that obtained with TGF beta 1, a related factor that also inhibits primary myosatellite cell proliferation. Attenuating the myostatin/activin (ie, Acvr2b) and TGF beta 1 receptor signaling pathways with the Alk4/5 and Alk5 inhibitors, SB431542 and SB505142, respectively, similarly attenuated proliferation induced by serum, myostatinor TGF beta 1 and in a dose-dependent manner. Inserum-free medium, both myostatin and TGF beta 1 stimulated Smad2 phosphorylation, but not that of Smad3, and a Smad3 inhibitor (SIS3) only inhibited proliferation in cells cultured in high serum. Thus, myostatin and TGF beta 1 stimulate C2C12 proliferation primarily via Smad2. These results together question the physiological relevance of the C2C12 model and previous studies using recombinant myostatin generated in bacteria. They also support the alternative use of primary myosatellite cells and recombinant myostatin generated in eukaryotes.
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