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Abstract
Three members of the family of protease-activated receptors (PARs), PARs-1, -3 and -4, have been identified as thrombin receptors. PAR-1 is expressed by primary myoblast cultures, and expression is repressed once myoblasts fuse to form myotubes. The current study was undertaken to investigate the hypothesis that thrombin inhibits myoblast fusion. Primary rodent myoblast cultures were deprived of serum to promote myoblast fusion and then cultured in the presence or absence of thrombin. Thrombin inhibited myoblast fusion, but another notable effect was observed; 50% of control cells were apoptotic within 24 h of serum deprivation, whereas less than 15% of thrombin-treated cells showed signs of apoptosis. Proteolysis was required for the effect of thrombin, but no other serine protease tested mimicked the action of thrombin. Neither a PAR-1- nor a PAR-4-activating peptide inhibited apoptosis or fusion, and myoblast cultures were negative for PAR-3 expression. Myoblasts exposed to thrombin for 1 h and then changed to medium without thrombin accumulated apoptosis inhibitory activity in their medium over the subsequent 20 h. Thus the protective action of thrombin appears to be effected through cleavage of an unidentified thrombin receptor, leading to secretion of a downstream apoptosis inhibitory factor. These results demonstrate that thrombin functions as a survival factor for myoblasts and is likely to play an important role in muscle development and repair.
Highlights
Thrombin is a trypsin-like serine proteinase that has a central role in hemostasis and thrombosis
protease-activated receptors (PARs)-1 is expressed by cultured myoblasts, but expression is repressed once myoblasts fuse to form myotubes [16]
Expression patterns of PAR-1 in primary cultures of myoblasts undergoing differentiation [16], as well as in developing muscle [17], led us to predict that thrombin inhibits myoblast fusion
Summary
Thrombin is a trypsin-like serine proteinase that has a central role in hemostasis and thrombosis. Results with mice genetically incapable of expressing PAR-1, have shown that not all of the effects of thrombin are mediated by this receptor, leading to the recent discovery of two additional thrombin receptors, PAR-3 and PAR-4, which are closely related to PAR-1 [7,8,9]. During the process of muscle development, myoblasts proliferate and undergo differentiation, fusing to form multinucleated myotubes. A number of growth factors have been shown to influence these processes in cultured myoblasts. Prothrombin is expressed in developing muscle [14], and in muscle cultures transcript levels and thrombin activity in the medium are increased by cholinergic stimulation [15]. Recent immunohistochemical studies in developing muscle indicate that loss of PAR-1 expression by myoblasts soon after fusion occurs in vivo [17]. Expression patterns of PAR-1 in cultured myoblasts led to the hypothesis that thrombin inhibits myoblast fusion. The results presented here document the effects of thrombin on fusion and apoptosis in primary myoblast cultures
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