Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation

Belanto, Joseph J.; Diaz-Perez, Silvia V.; Magyar, Clara E.; Maxwell, Michele M.; Yilmaz, Yasemin; Topp, Kasey; Boso, Guney; Jamieson, Catriona H.; Cacalano, Nicholas A.; Jamieson, Christina A.M.

doi:10.1016/j.nmd.2009.12.003

« Previous Next »Neuromuscular Disorders
Volume 20, Issue 2 , Pages 111-121, February 2010

Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation

Joseph J. Belanto
- Dept. of Urology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
- Dept. of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Silvia V. Diaz-Perez
- Dept. of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Clara E. Magyar
- Translational Pathology Core Laboratory, Dept. of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Michele M. Maxwell
- MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
Yasemin Yilmaz
- Dept. of Urology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Kasey Topp
- Dept. of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Guney Boso
- Dept. of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Catriona H. Jamieson
- Dept. of Medicine, Hematology/Oncology Division, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Nicholas A. Cacalano
- Dept. of Radiation Oncology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Christina A.M. Jamieson
- Dept. of Urology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
- Dept. of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA
- Corresponding author. Address: Dept. of Urology, David Geffen School of Medicine at UCLA, 4554 Gonda Center-708822, 695 Charles E. Young Dr. S., Los Angeles, CA 90095, USA. Tel.: +1 310 267 2469; fax: +1 310 794 5446.

Received 10 July 2009; received in revised form 30 November 2009; accepted 3 December 2009.

Abstract

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.

Keywords: Dysferlinopathy, Limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, Glucocorticoid, Myotube, C2C12, Myoblast differentiation, Dysferlin, Dexamethasone