Glucocorticoids are beneficial in many muscular dystrophies but they are ineffective in treating dysferlinopathy, a rare muscular dystrophy caused by loss of dysferlin. We sought to understand the molecular basis for this disparity by studying the effects of a glucocorticoid on differentiation of the myoblast cell line, C2C12, and dysferlin-deficient C2C12s. We found that pharmacologic doses of dexamethasone enhanced the myogenic fusion efficiency of C2C12s and increased the induction of dysferlin, along with specific myogenic transcription factors, sarcolemmal and structural proteins. In contrast, the dysferlin-deficient C2C12 cell line demonstrated a reduction in long myotubes and early induction of particular muscle differentiation proteins, most notably, myosin heavy chain. Dexamethasone partially reversed the defect in myogenic fusion in the dysferlin-deficient C2C12 cells. We hypothesize that a key therapeutic benefit of glucocorticoids may be the up-regulation of dysferlin as an important component of glucocorticoid-enhanced myogenic differentiation.
Bibliographical noteFunding Information:
We thank Drs. Michele M. Maxwell and Robert H. Brown, Jr. for generously providing the dysferlin-deficient C2C12 cells the development of which was supported by the C.B. Day Investment Company, ViaCell, Inc., the Thayer family and the Jain Foundation, Inc. We are grateful to Dr. Matthew J. Schibler for help with confocal microscopy. Confocal laser scanning microscopy was performed at the CNSI Advanced Light Microscopy/Spectroscopy Shared Resource Facility at UCLA, supported with funding from NIH-NCRR shared resources grant ( CJX1-443835-WS-29646 ) and NSF Major Research Instrumentation grant ( CHE-0722519 ). This work was supported by a grant from the Jain Foundation, Inc. (C.A.M. Jamieson) and NIH CBRP U19 (C.A.M. Jamieson, N. Cacalano) University of California at Los Angeles Center for Biological Radioprotectors grant U19 AI067769/NIAID.
Copyright 2010 Elsevier B.V., All rights reserved.
- Limb-girdle muscular dystrophy type 2B
- Miyoshi myopathy
- Myoblast differentiation