EDL morphology and function to b1/b2-KO mice and C57BL/6 controls. Uninjured EDL muscles from b1/b2-KO mice exhibited similar differences in morphology and function to TA muscles; i.e. decreased muscle mass, decreased twitch force and rate of contraction, and decreased absolute tetanic force when compared with C57BL/6 controls. Furthermore, EDL muscles from b1/b2-KO mice displayed similar deficits in regeneration at 7 days post-injury, confirming our findings in the TA muscle and further suggesting that the loss of both b1- and b2-ARs affects the earliest period of regeneration after myotoxic damage. Skeletal muscle regeneration is preceded by a well-defined and highly coordinated inflammatory response. Non-cytokine anti-inflammatory mediators are also able to modulate the inflammatory process, including glucocorticoids, adenosine, and endogenous b-agonists. b-ARs are not only present in skeletal muscle, but have also been detected on the surface of inflammatory cells such as mast cells, eosinophils, neutrophils and macrophages. To determine the degree of macrophage infiltration in regenerating muscles, we PF-4217903 examined the expression of the macrophage-specific markers F4/80 and CD68. The expression of both macrophage markers was significantly increased in b1/b2-KO than in controls. Previous studies have revealed that macrophages incubated with LPS have an increased expression of TNF-a and IL-6, which is inhibited by the b-agonist clenbuterol and that administering the b-AR antagonist propranolol can potentiate the release of inflammatory cytokines in vivo. Due to the well-characterized increase in TNF-a and IL-6 in response to inflammation, as well as the evidence that their expression is controlled to some degree by bAR signaling, we examined these two cytokines as a measure of inflammation and found that both cytokines were increased acutely after injury, with maximal expression at 2 days post-injury in control mice. This correlates well with previous studies from our laboratory where we have reported that oedema and immune cell infiltration are maximal at this time. In the present study, TNF-a was significantly more elevated in b1/b2-KO mice, and IL6 mRNA showed a non-significant trend toward higher expression than in regenerating muscles from control mice, suggesting that the acute immune response to injury in b1/b2-KO mice is exacerbated by the lack of b-ARs. Taken together, these data suggest that the inflammatory response and subsequent macrophage infiltration after injury is acutely higher in the b1/b2-KO mice compared with control. To ascertain whether the observed force deficits in muscles from b1/b2-KO mice at 7 days post-injury were associated with impaired myofiber regeneration, we assessed the expression of the myogenic regulatory factors responsible for muscle formation. Previous studies have demonstrated that clenbuterol represses the expression of MyoD and myogenin in denervated rat soleus muscles, and that clenbuterol administration increased myogenin expression in immobilized rat plantaris muscles. Clenbuterol administration also increased MyoD expression in rat soleus muscles.