GTS-21 attenuates loss of body mass, muscle mass, and function in rats having systemic inflammation with and without disuse atrophy

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 7-acetylcholine receptors (7nAChRs). Hypothesis tested was that modulation of inflammation by agonist GTS-21 (10mg/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 +/- 9g, 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 +/- 0.06g to 0.26 +/- 0.03g) and with superimposed disuse (0.18 +/- 0.04g); 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 7nAChR 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 7nAChR expression, and mitigates inflammation-mediated loss of BW, TMM, fiber size, and function.