β-Adrenoceptor signaling in regenerating skeletal muscle after β-agonist administration

Abstract

Stimulating the β-adrenoceptor (β-AR) signaling pathway can enhance the functional repair of skeletal muscle after injury, but long-term use of β-AR agonists causes β-AR downregulation, which may limit their therapeutic effectiveness. The aim was to examine β-AR signaling during early regeneration in rat fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles after bupivacaine injury and test the hypothesis that, during regeneration, β-agonist administration does not cause β-AR desensitization. Rats received either the β-AR agonist fenoterol (1.4 mg·kg−1·day−1 ip) or saline for 7 days postinjury. Fenoterol reduced β-AR density in regenerating soleus muscles by 42%. Regenerating EDL muscles showed a threefold increase in β-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 postinjury. Fenoterol attenuated this increase in regenerating EDL muscles but not soleus muscles. β-AR signaling mechanisms were assessed using AC stimulants (NaF, forskolin, and Mn2+). Although β-agonist treatment reduces β-AR density in regenerating muscles, these muscles can produce large cAMP responses relative to healthy (uninjured) muscles. Desensitization of β-AR signaling in regenerating muscles is prevented by altered rates of β-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 β-AR signaling to enhance muscle repair after injury.