Stimulating the -adrenoceptor (-AR) signaling pathway can enhance the functional repair of skeletal muscle after injury, but long-term use of -AR agonists causes -AR downregulation which may limit their therapeutic effectiveness. The aim was to examine -AR signaling during early regeneration in rat fast-twitch (EDL) and slow-twitch (soleus) muscles after bupivacaine injury, and test the hypothesis that during regeneration, -agonist administration does not cause -AR desensitization. Rats received either the -AR agonist fenoterol (1.4 mg/kg/day, i.p.) or saline for 7 days post-injury. Fenoterol reduced -AR density in regenerating soleus muscles by 42%. Regenerating EDL muscles showed a 3-fold increase in -AR density and again, these values were 43% lower with fenoterol treatment. An amplified adenylate cyclase (AC) response to isoproterenol was observed in cell membrane fragments from EDL and soleus muscles 7 days post-injury. Fenoterol attenuated this increase in regenerating EDL muscles, but not soleus muscles. -AR signaling mechanisms were assessed using AC stimulants (NaF, forskolin and Mn²⁺). Although -agonist treatment reduces -AR density in regenerating muscles, these muscles can produce large cAMP responses relative to healthy (uninjured) muscles. Desensitization of -AR signaling in regenerating muscles is prevented by altered rates of -AR synthesis and/or degradation, changes in G protein populations and coupling efficiency, and altered AC activity. These mechanisms have important therapeutic implications for modulating -AR signaling to enhance muscle repair after injury.