Zhu, Jinhong
(2006)
The role of myostatin in injured muscle.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Myostatin (MSTN), a member of the TGF-beta superfamily, was initially identified as a primary negative regulator of embryonic and postnatal muscle development. The MSTN gene is highly conserved among different species. Mutation of the MSTN gene results in a dramatic increase in skeletal muscle mass in mice, cattle, and humans. To date, most research has focused on the inhibitory role of MSTN on muscle growth, including the MSTN signaling pathway, the underlying mechanism of MSTN function, and the antagonists of MSTN. In this study, we identified a new property of MSTN. The project had 3 primary aims: (1) to characterize MSTN as a fibrogenesis stimulator; (2) to investigate the relationship between MSTN and TGF-beta1, and (3) to investigate the effect of decorin on MSTN. Our findings demonstrate that MSTN stimulates fibroblast proliferation and induces differentiation of fibroblasts into myofibroblasts in vitro. We also showed that MSTN knockout (MSTN-/-) mice develop significantly less fibrosis and exhibit better muscle regeneration than wild-type mice 2 weeks after gastrocnemius muscle (GM) laceration in vivo. In addition, we showed that TGF-beta1 stimulates MSTN expression in C2C12 myoblasts and, conversely, that MSTN stimulates the secretion of TGF-beta1 by C2C12 myoblasts in vitro. In vivo, MSTN injected into the GM stimulates myofibers to transiently co-express MSTN and TGF-beta1. Moreover, TGF-beta1 and MSTN colocalized in the necrotic myofibers shortly after GM laceration. Finally, our results showed that decorin, a natural inhibitor of TGF-beta1, blocks the effects of MSTN. After co-incubating cells with decorin and MSTN, we found that decorin reversed the stimulatory effect that MSTN had on preplate 1 (PP1) fibroblasts and blocked the inhibitory effect that MSTN had on myogenic cells. In vivo, the expression levels of decorin in regenerating muscle are related to MSTN levels. Immunohistochemistry revealed higher decorin expression in MSTN-/- regenerating muscle than in wild-type muscle. Our results suggest that the role of MSTN in injured skeletal muscle is more complex than initially defined: MSTN inhibits muscle growth. MSTN helps to regulate both extracellular matrix deposition in injured muscle and myogenesis. These findings have afforded us a better understanding of the role of MSTN in skeletal muscle healing and indicated that MSTN could be a viable pharmacologic target for antifibrogenesis therapy.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
5 June 2006 |
| Date Type: |
Completion |
| Defense Date: |
28 November 2005 |
| Approval Date: |
5 June 2006 |
| Submission Date: |
8 November 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
MSBeng - Master of Science in Bioengineering |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
fibrosis; muscle regeneration; myostatin |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11082005-160836/, etd-11082005-160836 |
| Date Deposited: |
10 Nov 2011 20:04 |
| Last Modified: |
15 Nov 2016 13:51 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9604 |
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