Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation.
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.
Belanto
Joseph J
JJ
Dept. of Urology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Diaz-Perez
Silvia V
SV
Magyar
Clara E
CE
Maxwell
Michele M
MM
Yilmaz
Yasemin
Y
Topp
Kasey
K
Boso
Guney
G
Jamieson
Catriona H
CH
Cacalano
Nicholas A
NA
Jamieson
Christina A M
CA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000073939:Dysferlin; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000819:agonists* / Q000096:biosynthesis / Q000172:deficiency; D051379:Mice; D024510:Muscle Development / Q000187:drug effects* / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C497505:Dysf protein, mouse; D000073939:Dysferlin; D005938:Glucocorticoids; D008565:Membrane Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D003907:Dexamethasone; D018995:Myosin Heavy Chains