Myostatin Inhibitors Affect MyoD and Myogenin Expression

Abstract

Myostatin (growth differentiation factor 8, GDF8) inhibits myogenesis and is a potential therapeutic target for muscular dystrophy and other myopathies. Animals with mutations in myostatin genes have increased muscle mass resulting from hypertrophy and hyperplasia. In this project three common myostatin inhibitors, GDF8 antibody, ActRIIB-Fc, and Alk4/5 inhibitor, were examined for their effects on agrin-induced acetylcholine receptor (AChR) clustering and expression of myogenic regulatory factors MyoD and myogenin. C2C12 cell cultures were maintained, myoblasts were differentiated into myotubes, and then cultures were exposed to motor neuron derived agrin to enhance AChR clustering. Untreated cultures were compared with cultures exposed to myostatin inhibitors at various concentrations. GDF8 antibody and Alk4/5 inhibitor decreased the frequency of agrin-induced AChR clustering with a dose response, while ActRIIB-Fc had no effect. Moreover, GDF8 antibody and ActRIIB-Fc increased MyoD expression and decreased myogenin expression, while Alk4/5 inhibitor decreased MyoD expression and increased myogenin expression. The differential effect of myostatin inhibitors on these events may be dependent on the different mechanisms of inhibition. Additional research could reveal if a myostatin inhibitor is an appropriate treatment for myopathies like muscular dystrophy. Jacqueline Sohn was supported by the Midwestern University Summer Fellowship Program. Wade A. Grow was supported by Midwestern University intramural funds.