Jh. Veerkamp et al., EFFECTS OF HMC-COA REDUCTASE INHIBITORS ON GROWTH AND DIFFERENTIATIONOF CULTURED RAT SKELETAL-MUSCLE CELLS, Biochimica et biophysica acta. Molecular basis of disease, 1315(3), 1996, pp. 217-222
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.