Abstract
Muscle changes of critical illness are attributed to systemic inflammatory responses and disuse atrophy. GTS-21 (3-(2,4-dimethoxy-benzylidene)anabaseine), also known as DMBX-A) is a synthetic derivative of the natural product anabaseine that acts as an agonist at α7-acetylcholine receptors (α7nAChRs). Hypothesis tested was that modulation of inflammation by agonist GTS-21 (10 mg/kg b.i.d. intraperitoneally) will attenuate body weight (BW) and muscle changes. Systemic sham inflammation was produced in 125 rats by Cornyebacterium parvum (C.p.) or saline injection on days 0/4/8. Seventy-four rats had one immobilized-limb producing disuse atrophy. GTS-21 effects on BW, tibialis muscle mass (TMM), and function were assessed on day 12. Systemically, methemoglobin levels increased 26-fold with C.p. (p < 0.001) and decreased significantly (p < 0.033) with GTS-21. Control BW increased (+ 30 ± 9 g, mean ± SD) at day 12, but decreased with C.p. and superimposed disuse (p = 0.005). GTS-21 attenuated BW loss in C.p. (p = 0.005). Compared to controls, TMM decreased with C.p. (0.43 ± 0.06 g to 0.26 ± 0.03 g) and with superimposed disuse (0.18 ± 0.04 g); GTS-21 ameliorated TMM loss to 0.32 ± 0.04 (no disuse, p = 0.028) and to 0.22 ± 0.03 (with disuse, p = 0.004). Tetanic tensions decreased with C.p. or disuse and GTS-21 attenuated tension decrease in animals with disuse (p = 0.006) and in animals with C.p. and disuse (p = 0.029). C.p.-induced 11-fold increased muscle α7nAChR expression was decreased by > 60% with GTS-21 treatment. In conclusion, GTS-21 modulates systemic inflammation, evidenced by both decreased methemoglobin levels and decrease of α7nAChR expression, and mitigates inflammation-mediated loss of BW, TMM, fiber size, and function.