Furthermore, expression of Myf5 was significantly increased in the regenerating muscles of b1/b2-KO mice than controls, indicating that myoblast proliferation was not WY 14643 compromised in the b1/b2-KO mice, and may be propagated for longer after muscle injury, than in control mice. The induction of MyoD and myogenin following injury was also exaggerated in the muscles of b1/b2 double-KO mice. Taken together, our MRF expression data suggest that myoblast proliferation and differentiation may be enhanced in b1/b2-KO mice at the expense of moderately delayed differentiation. This observation, consistent with what we had expected and described in a previous review, may explain why force producing capacity is impaired at 7 days post-injury in b1/b2-KO mice, but that muscles are capable of restoring functionality similar to control animals at 10 days post-injury. This rapid ‘catch up’ where the muscles of b1/b2-KO mice seemingly overcome their initial delayed regeneration and function impairment, is supported by our observations of cultured primary myoblasts from b1/b2-KO mice, where proliferation was enhanced and prolonged and differentiation was delayed. The present study utilized whole body b1/b2-KO mice, since to our knowledge there are no muscle-specific b1/b2-KO mice currently available. One concern with using the whole body b1/ b2-KO mouse is that any effects on muscle regeneration may be a consequence of perturbations of non-muscle physiological systems, rather than a direct effect on muscle regeneration per se. For example, the altered inflammatory response observed in the present study, while not a direct result of the muscle lacking bARs, undoubtedly influenced fiber regeneration. To obviate these concerns we isolated myoblasts from both b1/ b2-KO mice and C57BL/6 controls to examine myoblast proliferation and differentiation in the absence of confounding factors, and found that myoblasts isolated from b1/b2-KO mice proliferated more rapidly and differentiated far less effectively than those from C57BL/6 controls. While initially this may seem to be at odds with our MRF expression data from regenerating muscles, it must be remembered that even if myoblast differentiation was impaired in vivo, the vastly greater number of myoblasts present in the muscle due to the increased proliferation would still result in an overall increase in MyoD and myogenin expression in the muscle. Interestingly, we have previously documented a dramatic increase in the gene expression of adrb1 and adrb2 during the switch from proliferation to differentiation. Combined with the findings of the present study, these data support a role for b1/b2-ARs in inhibiting myoblast proliferation and promoting differentiation. Another concern with whole body b1/b2-KO mice is the potential for cardiovascular disturbances to influence muscle regeneration. We do not believe that the muscles from b1/b2-KO mice suffered a significant deficit in perfusion as this would have resulted in a constant inhibition of regeneration, whereas we observed a deficit in regeneration only at 7 days post-injury. In fact, the muscles from b1/b2-KO mice subsequently regenerated faster.