EFFECTS OF HMC-COA REDUCTASE INHIBITORS ON GROWTH AND DIFFERENTIATIONOF CULTURED RAT SKELETAL-MUSCLE CELLS

HMG-CoA reductase inhibitors have been associated with skeletal muscle myopathy, ranging from asymptomatic elevations of serum creatine kina se (CK) activity to rhabdomyolysis. In this study, we assessed the eff ects of addition of different concentrations of simvastatin and pravas tatin on growth and differentiation of cultured primary rat skeletal m uscle cells. Protein concentration, CK activity and percentage CK-MM, which is a parameter for maturation, were determined. Effects were gen erally stronger if inhibitors were added to both growth and differenti ation medium rather than only to differentiation medium. Addition of 2 5 mu M pravastatin caused only a decrease of CK activity. Addition of 1-5 mu M simvastatin resulted in a decrease of protein concentration, CK activity and percentage CK-MM, whereas 25 mu M simvastatin resulted in cell death. Addition of mevalonic acid or cholesterol could not pr event the effects of 1 mu M simvastatin. In addition, 1 mu M simvastat in did not influence the cholesterol and phospholipid content of the c ells. Superfusion of cultured cells with simvastatin concentrations of 10 mu M and higher caused a transient increase of the cytoplasmic cal cium concentration followed by an apparent second rise and cell punctu re. The results indicate that HMG-CoA reductase inhibitors may affect skeletal muscle cell regeneration in vivo by a direct toxic effect on growth and differentiation.